{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-06-03", "results": { "skip": 0, "limit": 1, "total": 1 } }, "results": [ { "spl_product_data_elements": [ "Tecentriq Hybreza atezolizumab and hyaluronidase-tqjs ATEZOLIZUMAB ATEZOLIZUMAB HYALURONIDASE (HUMAN RECOMBINANT) HYALURONIDASE (HUMAN RECOMBINANT) HISTIDINE SUCROSE POLYSORBATE 20 METHIONINE ACETIC ACID WATER" ], "recent_major_changes": [ "Indications and Usage ( 1.2 , 1.5 ) 11/2025 Indications and Usage ( 1.6 ) 05/2026 Dosage and Administration ( 2.2 , 2.3 ) 11/2025 Dosage and Administration ( 2.1 , 2.3 ) 05/2026 Warnings and Precautions ( 5.1 ) 05/2026 Warnings and Precautions ( 5.2 ) 08/2025" ], "recent_major_changes_table": [ "
Indications and Usage (1.2, 1.5)11/2025
Indications and Usage (1.6)05/2026
Dosage and Administration (2.2, 2.3)11/2025
Dosage and Administration (2.1, 2.3)05/2026
Warnings and Precautions (5.1)05/2026
Warnings and Precautions (5.2)08/2025
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE TECENTRIQ HYBREZA is a combination of atezolizumab, a programmed death-ligand 1 (PD-L1) blocking antibody, and hyaluronidase, an endoglycosidase indicated: Non-Small Cell Lung Cancer (NSCLC) as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-authorized test. ( 1.1 ) for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ HYBREZA. ( 1.1 ) Small Cell Lung Cancer (SCLC) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). ( 1.2 ) in combination with lurbinectedin, for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ HYBREZA or intravenous atezolizumab, and carboplatin plus etoposide. ( 1.2 ) Hepatocellular Carcinoma (HCC) in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy. ( 1.3 ) Melanoma in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test. ( 1.4 ) Alveolar Soft Part Sarcoma (ASPS) for the treatment of adult patients and pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic ASPS. ( 1.5 ) Muscle Invasive Bladder Cancer (MIBC) as adjuvant treatment of adult patients with MIBC after cystectomy who have circulating tumor DNA molecular residual disease (ctDNA MRD) as determined by an FDA-authorized test. ( 1.6 ) 1.1 Non-Small Cell Lung Cancer TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1) ] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA- authorized test [see Dosage and Administration (2.1) ]. TECENTRIQ HYBREZA, as monotherapy, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]) , as determined by an FDA- authorized test, with no EGFR or ALK genomic tumor aberrations [see Dosage and Administration (2.1) ]. TECENTRIQ HYBREZA, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. TECENTRIQ HYBREZA, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. TECENTRIQ HYBREZA, as monotherapy, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ HYBREZA. 1.2 Small Cell Lung Cancer TECENTRIQ HYBREZA, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). TECENTRIQ HYBREZA, in combination with lurbinectedin, is indicated for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ HYBREZA or intravenous atezolizumab, carboplatin and etoposide. 1.3 Hepatocellular Carcinoma TECENTRIQ HYBREZA, in combination with bevacizumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy. 1.4 Melanoma TECENTRIQ HYBREZA, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test [see Dosage and Administration (2.1) ] . 1.5 Alveolar Soft Part Sarcoma TECENTRIQ HYBREZA, as monotherapy, is indicated for the treatment of adult patients and pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic alveolar soft part sarcoma (ASPS). 1.6 Muscle Invasive Bladder Cancer TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment of adult patients with muscle invasive bladder cancer (MIBC) after cystectomy who have circulating tumor DNA molecular residual disease (ctDNA MRD) as determined by an FDA-authorized test [see Dosage and Administration (2.1) ] ." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. ( 2.2 ) TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. ( 2.2 ) Do not administer TECENTRIQ HYBREZA intravenously. ( 2.2 ) The recommended dosage for adult patients and pediatric patients (12 years and older who weigh 40 kg or greater) is: TECENTRIQ HYBREZA 15 mL (1,875 mg atezolizumab and 30,000 units hyaluronidase) subcutaneously into the thigh over approximately 7 minutes every 3 weeks. ( 2.2 ) TECENTRIQ HYBREZA must be administered by a healthcare professional. ( 2.2 ) NSCLC Dosage In the adjuvant setting , administer TECENTRIQ HYBREZA following resection and up to 4 cycles of platinum-based chemotherapy every 3 weeks for up to 1 year. ( 2.3 ) In the metastatic setting , administer TECENTRIQ HYBREZA every 3 weeks. ( 2.3 ) When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. ( 2.3 ) SCLC Dosage Administer TECENTRIQ HYBREZA every 3 weeks. Administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day. ( 2.3 ) HCC Dosage Administer TECENTRIQ HYBREZA every 3 weeks. Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks. ( 2.3 ) Melanoma Dosage Following completion of a 28-day cycle of cobimetinib and vemurafenib, administer TECENTRIQ HYBREZA every 3 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. ( 2.3 ) ASPS Dosage Administer TECENTRIQ HYBREZA every 3 weeks. ( 2.3 ) MIBC Dosage Administer TECENTRIQ HYBREZA after cystectomy every 3 weeks for up to 1 year. ( 2.3 ) 2.1 Patient Selection for Treatment of Non-Small Cell Lung Cancer, Melanoma and Muscle Invasive Bladder Cancer Select adult patients with: Stage II to IIIA NSCLC for adjuvant treatment with TECENTRIQ HYBREZA as a monotherapy (following tumor resection and platinum-based chemotherapy) based on PD-L1 expression on tumor cells [see Clinical Studies (14.1) ]. Metastatic NSCLC for first-line treatment with TECENTRIQ HYBREZA as monotherapy based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.1) ]. Unresectable or metastatic melanoma for treatment with TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib after confirming the presence of a BRAF V600 mutation [see Clinical Studies (14.4) ]. MIBC for treatment with TECENTRIQ HYBREZA, as a monotherapy based on detection of ctDNA MRD in plasma via serial testing between six weeks and one year after cystectomy [see Clinical Studies (14.6) ]. Information on FDA-authorized tests for the determination of PD-L1 expression in metastatic NSCLC, for detection of BRAF V600 mutations in melanoma, or for the determination of ctDNA MRD status in MIBC is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Important Dosage and Administration Information TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab. Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages. Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose. Adult patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose. Pediatric patients 12 years of age and older who weigh 40 kg or greater and are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose [see Indications and Usage (1.5) ]. Pediatric patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose. TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. Administer over approximately 7 minutes. Inject in healthy skin and never into areas where the skin is red, bruised, tender, or hard. When possible, alternate injections between the left and right thigh. Ensure the injection site is at least 2.5 cm from the previous site. Do not administer TECENTRIQ HYBREZA intravenously. TECENTRIQ HYBREZA must be administered by a healthcare professional. Do not administer the remaining volume in the tubing to the patient. If using concomitant subcutaneous drugs, administer at sites other than the thighs. 2.3 Recommended Dosage and Administration Instructions The recommended dosage of TECENTRIQ HYBREZA in adult patients and pediatric patients (12 years of age and older who weigh 40 kg or greater) is one 15 mL injection (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase, referred to as TECENTRIQ HYBREZA) administered subcutaneously in the thigh over approximately 7 minutes every 3 weeks. The recommended dosage for pediatric patients 12 years of age and older who weigh less than 40 kg has not been established [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) ]. Administration instructions for TECENTRIQ HYBREZA as monotherapy and in combination with other therapeutic agents are presented in Table 1 . For the recommended dosage of each therapeutic agent administered in combination with TECENTRIQ HYBREZA refer to the product's respective Prescribing Information. Table 1: TECENTRIQ HYBREZA Administration Instructions and Duration of Therapy Indication Administration Instructions for TECENTRIQ HYBREZA Duration of Therapy Adjuvant Treatment of Non-Small Cell Lung Cancer Administer TECENTRIQ HYBREZA as monotherapy Up to one year, unless there is disease recurrence or unacceptable toxicity Metastatic Non-Small Cell Lung Cancer Until disease progression or unacceptable toxicity Non-Small Cell Lung Cancer Administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. Until disease progression or unacceptable toxicity Small Cell Lung Cancer Administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day. Hepatocellular Carcinoma Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks. Melanoma Prior to initiating TECENTRIQ HYBREZA, patients should receive the following 28-day treatment cycle of cobimetinib and vemurafenib: Days 1 to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice daily Days 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily Alveolar Soft Part Sarcoma Administer TECENTRIQ HYBREZA as monotherapy Until disease progression or unacceptable toxicity Muscle Invasive Bladder Cancer Administer TECENTRIQ HYBREZA as monotherapy Up to one year, unless there is disease recurrence or unacceptable toxicity 2.4 Dosage Modifications for Adverse Reactions No dose reduction for TECENTRIQ HYBREZA is recommended. In general, withhold TECENTRIQ HYBREZA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TECENTRIQ HYBREZA for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the daily corticosteroid dosage to 10 mg or less of prednisone or equivalent corticosteroid dosage within 12 weeks of initiating corticosteroids. Dosage modifications for TECENTRIQ HYBREZA for adverse reactions that require management different from these general guidelines are summarized in Table 2 . Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 5 Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids Grades 3 or 4 Permanently discontinue Colitis Grades 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ HYBREZA based on recommendations for hepatitis with no liver involvement Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grades 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grades 2 or 3 increased blood creatinine Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis or pericarditis Grades 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grades 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Grades 1 or 2 Pause or slow the rate of injection Premedication with antipyretic and antihistamines may be considered for subsequent doses. Grades 3 or 4 Permanently discontinue 2.5 Preparation Instructions TECENTRIQ HYBREZA does not contain any antimicrobial preservative. If the TECENTRIQ HYBREZA dose is not administered immediately, refer to \"Storage Instructions\" [see Dosage and Administration (2.6) ]. Remove the vial from the refrigerator and allow the solution to acclimate to room temperature. Visually inspect for particulate matter and discoloration prior to administration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake, freeze, or dilute. The unpunctured vial may be stored at room temperature in ambient light for a maximum of 4 hours prior to the preparation for administration. Use an 18-gauge transfer needle and syringe to withdraw the entire contents of the TECENTRIQ HYBREZA solution from the vial. Discard the vial and any residual drug remaining. TECENTRIQ HYBREZA is compatible with stainless steel transfer and injection needles, and polypropylene, polycarbonate, polyvinyl chloride, and polyurethane syringe material and subcutaneous administration sets. Remove the transfer needle from the syringe and replace it with a subcutaneous administration set (e.g. winged/butterfly) containing 23-gauge, 24-gauge, or 25-gauge hypodermic needle and with a priming volume that does not exceed 0.5 mL for administration. Prime the subcutaneous administration line with TECENTRIQ HYBREZA to eliminate the air in the line and stop when the fluid reaches the needle. Ensure the syringe contains exactly 15 mL of TECENTRIQ HYBREZA after priming the administration line by expelling any excess volume from the syringe. Administer immediately to avoid needle clogging. Discard any unused portion remaining. 2.6 Storage Instructions Do not store the prepared syringe that has been attached to the already-primed subcutaneous administration set. If the prepared syringe containing TECENTRIQ HYBREZA is not for immediate use, do not attach a subcutaneous administration set. The capped syringe may be stored at room temperature [at up to 25°C (77°F)] in ambient room lighting for up to 8 hours and in the refrigerator [2°C to 8°C (36°F to 46°F)] for up to 72 hours. Do not shake or freeze. If the prepared syringe is stored at 2°C to 8°C (36°F to 46°F), allow the syringe to acclimate to room temperature prior to administration." ], "dosage_and_administration_table": [ "
Table 1: TECENTRIQ HYBREZA Administration Instructions and Duration of Therapy
IndicationAdministration Instructions for TECENTRIQ HYBREZADuration of Therapy
Adjuvant Treatment of Non-Small Cell Lung CancerAdminister TECENTRIQ HYBREZA as monotherapyUp to one year, unless there is disease recurrence or unacceptable toxicity
Metastatic Non-Small Cell Lung CancerUntil disease progression or unacceptable toxicity
Non-Small Cell Lung CancerAdminister TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day.Until disease progression or unacceptable toxicity
Small Cell Lung CancerAdminister TECENTRIQ HYBREZA prior to chemotherapy when given on the same day.
Hepatocellular CarcinomaAdminister TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks.
MelanomaPrior to initiating TECENTRIQ HYBREZA, patients should receive the following 28-day treatment cycle of cobimetinib and vemurafenib:Days 1 to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice dailyDays 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily
Alveolar Soft Part SarcomaAdminister TECENTRIQ HYBREZA as monotherapyUntil disease progression or unacceptable toxicity
Muscle Invasive Bladder CancerAdminister TECENTRIQ HYBREZA as monotherapyUp to one year, unless there is disease recurrence or unacceptable toxicity
", "
Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse ReactionSeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version 5Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
PneumonitisGrade 2WithholdResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids
Grades 3 or 4Permanently discontinue
ColitisGrades 2 or 3Withhold
Grade 4Permanently discontinue
Hepatitis with no tumor involvement of the liverAST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold
AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue
Hepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ HYBREZA based on recommendations for hepatitis with no liver involvementBaseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULNWithhold
AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULNPermanently discontinue
EndocrinopathiesGrades 3 or 4Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal DysfunctionGrades 2 or 3 increased blood creatinineWithhold
Grade 4 increased blood creatininePermanently discontinue
Exfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESSWithhold
Confirmed SJS, TEN, or DRESSPermanently discontinue
Myocarditis or pericarditisGrades 2, 3, or 4Permanently discontinue
Neurological ToxicitiesGrade 2Withhold
Grades 3 or 4Permanently discontinue
Other Adverse Reactions
Infusion-Related Reactions [see Warnings and Precautions (5.2)]Grades 1 or 2Pause or slow the rate of injection Premedication with antipyretic and antihistamines may be considered for subsequent doses.
Grades 3 or 4Permanently discontinue
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 1,875 mg atezolizumab and 30,000 units hyaluronidase per 15 mL (125 mg and 2,000 units per mL) clear to slightly opalescent, and colorless to slightly yellow solution in a single-dose vial. Injection : 1,875 mg atezolizumab and 30,000 units hyaluronidase per 15 mL (125 mg/2,000 units per mL) solution in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients. TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or any of its excipients. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. ( 5.1 ) Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue based on severity and type of reaction. Infusion-Related Reactions : Pause or slow the rate of injection, or permanently discontinue based on severity of the reaction. ( 5.2 ) Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. ( 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions TECENTRIQ HYBREZA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ]. In general, if TECENTRIQ HYBREZA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis TECENTRIQ HYBREZA can cause immune-mediated pneumonitis, including fatal adverse reactions. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 2% (5/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] , including Grade 2 (0.8%), and Grade 1 (1.2%) events. Pneumonitis led to the withholding of TECENTRIQ HYBREZA in one patient. Systemic corticosteroids were required in 40% (2/5) patients with pneumonitis who received TECENTRIQ HYBREZA as monotherapy. Pneumonitis resolved in both patients. The single patient in whom TECENTRIQ HYBREZA was withheld for pneumonitis reinitiated TECENTRIQ HYBREZA after symptom improvement. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1) ], including Grade 3 (1.3%) and Grade 2 (7%) adverse reactions. Pneumonitis led to permanent discontinuation of intravenous atezolizumab in 2.6% of patients and withholding of intravenous atezolizumab in 7.4% of patients. Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom intravenous atezolizumab was withheld for pneumonitis, 10 reinitiated intravenous atezolizumab after symptom improvement; of these, 50% had recurrence of pneumonitis. Immune-Mediated Colitis TECENTRIQ HYBREZA can cause immune-mediated colitis, including Grade 3 adverse reactions. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal bleeding. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-Mediated Hepatitis TECENTRIQ HYBREZA can cause immune-mediated hepatitis, including fatal adverse reactions. Immune-mediated hepatitis occurred in 1.2% (3/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] , including Grade 1 (0.4%) and Grade 3 (0.8%) events. Hepatitis led to the withholding of TECENTRIQ HYBREZA in 0.4% of patients. Systemic corticosteroids were required in 67% (2/3) of patients with hepatitis who received TECENTRIQ HYBREZA as monotherapy. Hepatitis resolved in 1 of the 3 patients. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1) ], including Grade 4 (1.3%), Grade 3 (1.7%) and Grade 2 (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of intravenous atezolizumab in 2.2% and withholding of intravenous atezolizumab in 1.7% of patients. Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom intravenous atezolizumab was withheld for hepatitis, 3 reinitiated intravenous atezolizumab after symptom improvement; of these, 33% had recurrence of hepatitis. Immune-Mediated Endocrinopathies Adrenal Insufficiency: TECENTRIQ HYBREZA can cause primary or secondary adrenal insufficiency, including Grade 3 adverse reactions. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ] . Immune-mediated adrenal insufficiency occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] , including Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to the withholding of TECENTRIQ HYBREZA in both patients. Systemic corticosteroids were required in 50% (1/2) of patients with adrenal insufficiency who received TECENTRIQ HYBREZA as monotherapy; this single patient remained on systemic corticosteroids. Hypophysitis: TECENTRIQ HYBREZA can cause immune-mediated hypophysitis, including Grade 2 adverse reactions. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ] . Immune-mediated hypophysitis occurred in 0.4% (1/247) of patients with locally advanced or metastatic NSCLC in the IMscin001 trial [see Adverse Reactions (6.1) ] receiving TECENTRIQ HYBREZA as monotherapy, including Grade 1 (0.4%) adverse reactions. Hypophysitis led to the withholding of TECENTRIQ HYBREZA in this patient. Thyroid Disorders: TECENTRIQ HYBREZA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ] . Thyroiditis: Immune-mediated thyroiditis occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] , including Grade 2 (0.4%) adverse reactions. Thyroiditis resolved in 50% of patients. Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2% (5/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] , including Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to withholding of TECENTRIQ HYBREZA in 0.8% of patients. Anti-thyroid therapy was required in 40% (2/5) of patients with hyperthyroidism who received TECENTRIQ HYBREZA as monotherapy. Of these 2 patients, one remained on anti-thyroid treatment. Of the 2 patients in whom TECENTRIQ HYBREZA was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ HYBREZA; this patient did not have recurrence of hyperthyroidism. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Hyperthyroidism occurred in 19% (43/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1) ], including Grade 3 (0.9%) and Grade 2 (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom intravenous atezolizumab was withheld for hyperthyroidism, 18 patients reinitiated intravenous atezolizumab; of these, 28% had recurrence of hyperthyroidism. Hypothyroidism: TECENTRIQ HYBREZA can cause immune-mediated hypothyroidism, including Grade 4 adverse reactions. Immune-mediated hypothyroidism occurred in 10% (25/247) of patients with locally advanced or metastatic NSCLC who received TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] . Hormone replacement was required in 68% (17/25) of patients with hypothyroidism who received TECENTRIQ HYBREZA as monotherapy. Two patients with hypothyroidism remained on thyroid hormone replacement. Intravenous Atezolizumab in Combination with Platinum-based Chemotherapy: Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC (N = 2223) or SCLC (N = 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133 receiving intravenous atezolizumab in combination with platinum-based chemotherapy, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of intravenous atezolizumab in 0.1% and withholding of intravenous atezolizumab in 1.6% of patients. Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 9 reinitiated intravenous atezolizumab after symptom improvement. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Hypothyroidism occurred in 26% (60/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1) ] , including Grade 2 (9.1%) adverse reactions. Hypothyroidism led to withholding of intravenous atezolizumab in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 6 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 4 reinitiated intravenous atezolizumab after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis: TECENTRIQ HYBREZA can cause type 1 diabetes mellitus, including Grade 3 adverse reactions and diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ] . Immune-Mediated Nephritis with Renal Dysfunction TECENTRIQ HYBREZA can cause immune-mediated nephritis, including Grade 3 adverse reactions. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1) ], including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 0.9% of patients. Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all 3 of these patients. Of the 2 patients in whom intravenous atezolizumab was withheld for nephritis, both reinitiated intravenous atezolizumab after symptom improvement and neither had recurrence of nephritis. Immune-Mediated Dermatologic Adverse Reactions TECENTRIQ HYBREZA can cause immune-mediated rash or dermatitis, including Grade 3 and fatal adverse reactions. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3) ] . One fatal case of an immune-mediated dermatologic adverse reaction, due to TEN, occurred (0.4%, 1/247) in patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1) ] . Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients receiving intravenous atezolizumab or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular : Myocarditis, pericarditis, vasculitis. Nervous System : Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular : Uveitis, iritis, and other ocular inflammatory toxicities occurred. Some cases were associated with retinal detachment. Various grades of visual impairment, including blindness, occurred. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal : Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue : Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine : Hypoparathyroidism. Hematologic/Immune : Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions. 5.2 Infusion-Related Reactions TECENTRIQ HYBREZA can cause severe or life-threatening infusion-related reactions, including Grade 3 adverse reactions and anaphylaxis. Monitor for signs and symptoms of infusion-related reactions. Pause, slow the rate of, or permanently discontinue TECENTRIQ HYBREZA based on the severity [see Dosage and Administration (2.3) ] . For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. 5.3 Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockage and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ HYBREZA. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for 5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors [see Warnings and Precautions (5.3) ] Most common adverse reactions (AR) (≥ 10%) with TECENTRIQ HYBREZA as monotherapy in patients with NSCLC were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. ( 6.1 ) Safety of TECENTRIQ HYBREZA for the approved NSCLC, EC-SCLC, HCC, melanoma, ASPS, and MIBC indications is based on safety of intravenous atezolizumab in these populations. Most common AR with intravenous atezolizumab are presented below by indication and regimen ( 6.1 ): Most common AR (≥ 20%) as monotherapy were: First-line NSCLC : fatigue/asthenia. Metastatic NSCLC : fatigue/asthenia, cough, decreased appetite, dyspnea, and myalgia/pain. ASPS : musculoskeletal pain, fatigue, rash, cough, headache, nausea, hypertension, vomiting, constipation, dyspnea, dizziness, hemorrhage, diarrhea, insomnia, abdominal pain hypothyroidism, pyrexia, anxiety, arrhythmia and decreased appetite. MIBC: urinary tract infection. Most common AR (≥ 20%) in combination with other antineoplastic drugs were: NSCLC (with bevacizumab, paclitaxel, and carboplatin): neuropathy fatigue/asthenia, alopecia, myalgia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, rash, cough. Non-squamous NSCLC (with paclitaxel protein-bound and carboplatin): fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, alopecia, dyspnea, decreased appetite, cough, vomiting and rash. SCLC (with chemotherapy): fatigue/asthenia, nausea, alopecia, decreased appetite, constipation and vomiting. HCC (with bevacizumab): hypertension, fatigue and proteinuria. Melanoma (with cobimetinib and vemurafenib): rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction. To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions of TECENTRIQ HYBREZA in Adult Patients with NSCLC The safety of TECENTRIQ HYBREZA was evaluated in IMscin001, open-label, multi-center, international, randomized trial for patients with locally advanced or metastatic NSCLC who have not been exposed to cancer immunotherapy and who have had disease progression on prior platinum-based therapy [see Clinical Studies (14.1) ] . Patients with previously treated metastatic non-small cell lung cancer (NSCLC) either received TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously into the thigh over approximately 7 minutes every 3 weeks or intravenous atezolizumab every 3 weeks until disease progression or unacceptable toxicity. Among 247 patients who received TECENTRIQ HYBREZA, 32% were exposed for 6 months or longer and 8% were exposed for greater than one year. The median age was 64 years (range: 27 to 85); 69% male; 67% White, 22% Asian, 0.8% Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers. Serious adverse reactions occurred in 19% of patients who received TECENTRIQ HYBREZA. Serious adverse reactions (> 1%) included pneumonia, myocardial infarction, and pleural effusion. Fatal adverse reactions occurred in 6% of patients who received TECENTRIQ HYBREZA, including pneumonia (2.4%), myocardial infarction (1.2%), head injury (0.4%), ischemic stroke (0.4%), pleural effusion (0.4%), pulmonary embolism (0.4%), respiratory tract infection (0.4%), sepsis (0.4%), and toxic epidermal necrolysis (0.4%). Permanent discontinuation of TECENTRIQ HYBREZA due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ HYBREZA in > 1% of patients included pneumonia (2%). Dosage interruptions of TECENTRIQ HYBREZA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in > 1% of patients were COVID-19 (4.9%), increased aspartate aminotransferase (2.8%), increased alanine aminotransferase (2.4%), pneumonia (2.4%), anemia (1.6%), dyspnea (1.6%), fatigue (1.2%), and viral respiratory tract infection (1.2%). The most common adverse reactions of any grade (occurring in ≥ 10% of patients) were fatigue (19%), musculoskeletal pain (15%), cough (13%), dyspnea (12%), and decreased appetite (11%). Tables 3 and 4 summarize adverse reactions and selected laboratory abnormalities, respectively in TECENTRIQ HYBREZA-treated patients in IMscin001. Table 3: Adverse Reactions (≥ 10%) in Adult Patients with Locally Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001 Adverse Reaction Graded per NCI CTCAE v5.0 TECENTRIQ HYBREZA n = 247 Intravenous Atezolizumab n = 124 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) General Disorder and Administration Site Conditions Fatigue Composite term includes fatigue, asthenia 19 0.8 18 0 Musculoskeletal and Connective Tissue disorders Musculoskeletal Pain Composite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain 15 0.4 13 3.2 Respiratory, Thoracic and Mediastinal Cough Composite term includes cough, productive cough 13 0 7 0 Dyspnea Composite term includes dyspnea, dyspnea at rest, dyspnea exertional 12 1.2 15 1.6 Metabolism and Nutrition Disorders Decreased appetite 11 0 11 0 Clinically relevant adverse reactions in < 10% of patients who received TECENTRIQ HYBREZA were local injection site reactions (4.5%) and pyrexia (1.2%). Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001 Laboratory Abnormality Graded per NCI CTCAE v5.0 TECENTRIQ HYBREZA (n = 247) Intravenous Atezolizumab (n = 124) All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ HYBREZA (48-233) and intravenous atezolizumab (19-117) Hematology Decreased Hemoglobin 67 6 63 5 Decreased lymphocytes 37 9 45 15 Chemistry Decreased Sodium 46 3.9 47 5 Decreased Albumin 34 2.2 27 0 Increased Alkaline Phosphatase 33 1.3 27 0 Increased AST 28 2.6 32 2.6 Increased ALT 28 2.6 23 1.7 Decreased calcium 22 2.6 23 0.9 Increased calcium 20 2.6 24 1.7 Increased potassium 21 1.7 22 1.7 Increased INR 20 2 23 0 Increased Creatinine 19 1.7 26 0.9 Adverse Reactions in Adult Patients with NSCLC Treated with Intravenous Atezolizumab The safety of TECENTRIQ HYBREZA for its approved NSCLC indications [see Indications and Usage (1.1) ] has been established in adequate and well-controlled studies of intravenous atezolizumab for the: adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells (IMpower010 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study). Below is a description of adverse reactions of intravenous atezolizumab in these adequate and well-controlled NSCLC studies. Non-Small Cell Lung Cancer (NSCLC) Adjuvant Treatment of Early-stage NSCLC IMpower010 The safety of intravenous atezolizumab was evaluated in IMpower010, a multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors ≥ 4 cm) -IIIA NSCLC who had complete tumor resection and received up to 4 cycles of cisplatin-based adjuvant chemotherapy. Patients received intravenous atezolizumab 1200 mg every 3 weeks (n = 495) for 1 year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.1) ]. The median number of cycles received was 16 (range: 1, 16). Fatal adverse reactions occurred in 1.8% of patients receiving intravenous atezolizumab; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each). Serious adverse reactions occurred in 18% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%). Intravenous atezolizumab was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (≥ 1%) leading to intravenous atezolizumab discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotransferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 29% of patients; the most common (> 1%) were rash (3.0%), hyperthyroidism (2.8%), hypothyroidism (1.6%), increased AST (1.6%), pyrexia (1.6%), increased ALT (1.4%), upper respiratory tract infection (1.4%), headache (1.2%), peripheral neuropathy (1.2%), and pneumonia (1.2%). Tables 5 and 6 summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower010. Table 5: Adverse Reactions Occurring in ≥ 10% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010 Adverse Reaction Graded per NCI CTCAE v4.0 Intravenous Atezolizumab N = 495 Best Supportive Care N = 495 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Skin and Subcutaneous Tissue Rash Includes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform 17 1.2 1.4 0 Pruritus 10 0 0.6 0 Endocrine Disorders Hypothyroidism Includes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased 14 0 0.6 0 Respiratory, Thoracic and Mediastinal Cough Productive cough, upper airway cough syndrome, cough 16 0 11 0 General Pyrexia Includes pyrexia, body temperature increased, hyperthermia 14 0.8 2.2 0.2 Fatigue Includes fatigue, asthenia 14 0.6 5 0.2 Nervous System Disorders Peripheral neuropathy Includes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy 12 0.4 7 0.2 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain 14 0.8 9 0.2 Arthralgia Includes arthralgia, arthritis 11 0.6 6 0 Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010 Laboratory Abnormality Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0). Intravenous Atezolizumab The denominators used to calculate the rate varied from 78–480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value. Best Supportive Care All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Chemistry Increased aspartate aminotransferase 34 2.5 18 0 Increased alanine aminotransferase 30 3.3 19 0.4 Hyperkalemia 24 3.5 15 2.5 Increased blood creatinine 31 0.2 23 0.2 Metastatic Chemotherapy-Naïve NSCLC IMpower110 The safety of intravenous atezolizumab was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received intravenous atezolizumab 1200 mg every 3 weeks (n = 286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n = 263) until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ]. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area). The median duration of exposure to intravenous atezolizumab was 5.3 months (0 to 33 months). Fatal adverse reactions occurred in 3.8% of patients receiving intravenous atezolizumab; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each). Serious adverse reactions occurred in 28% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%). Intravenous atezolizumab was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (≥ 2 patients) leading to intravenous atezolizumab discontinuation were peripheral neuropathy and pneumonitis. Adverse reactions leading to interruption of intravenous atezolizumab occurred in 26% of patients; the most common (> 1%) were ALT increased (2.1%), AST increased (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%) and upper respiratory tract infection (1.4%). Tables 7 and 8 summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower110. Table 7: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower110 Adverse Reaction Intravenous Atezolizumab N = 286 Platinum-Based Chemotherapy N = 263 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 Gastrointestinal Nausea 14 0.3 34 1.9 Constipation 12 1.0 22 0.8 Diarrhea 11 0 12 0.8 General Fatigue/Asthenia 25 1.4 34 4.2 Pyrexia 14 0 9 0.4 Metabolism and Nutrition Decreased appetite 15 0.7 19 0 Respiratory, Thoracic and Mediastinal Dyspnea 14 0.7 10 0 Cough 12 0.3 10 0 Table 8: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower110 Laboratory Abnormality Intravenous Atezolizumab Platinum-Based Chemotherapy All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: intravenous atezolizumab (range: 278–281); platinum-based chemotherapy (range: 256–260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range. Hematology Anemia 69 1.8 94 20 Lymphopenia 47 9 59 17 Chemistry Hypoalbuminemia 48 0.4 39 2 Increased alkaline phosphatase 46 2.5 42 1.2 Hyponatremia 44 9 36 7 Increased ALT 38 3.2 32 0.8 Increased AST 36 3.2 32 0.8 Hyperkalemia 29 3.9 36 2.7 Hypocalcemia 24 1.4 24 2.7 Increased blood creatinine 24 0.7 33 1.5 Hypophosphatemia 23 3.6 21 2 First-Line Metastatic Non-squamous NSCLC IMpower150 The safety of intravenous atezolizumab with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, a multicenter, international, randomized, open-label trial in which 393 chemotherapy-naïve patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m 2 or 200 mg/m 2 , and carboplatin AUC 6 mg/mL/min intravenously every 3 weeks for a maximum of 4 or 6 cycles, followed by intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ]. The median duration of exposure to intravenous atezolizumab was 8.3 months in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin. Fatal adverse reactions occurred in 6% of patients receiving intravenous atezolizumab; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection. Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (> 2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis. Intravenous atezolizumab was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 48%; the most common (> 1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria. Tables 9 and 10 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin in IMpower150. Table 9: Adverse Reactions Occurring in ≥ 15% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150 Adverse Reaction Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin N = 393 Bevacizumab, Paclitaxel and Carboplatin N = 394 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 Nervous System Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 56 3 47 3 Headache 16 0.8 13 0 General Fatigue/Asthenia 50 6 46 6 Pyrexia 19 0.3 9 0.5 Skin and Subcutaneous Tissue Alopecia 48 0 46 0 Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 23 2 10 0.3 Musculoskeletal and Connective Tissue Myalgia/Pain Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 42 3 34 2 Arthralgia 26 1 22 1 Gastrointestinal Nausea 39 4 32 2 Diarrhea Includes diarrhea, gastroenteritis, colitis, enterocolitis 33 6 25 0.5 Constipation 30 0.3 23 0.3 Vomiting 19 2 18 1 Metabolism and Nutrition Decreased appetite 29 4 21 0.8 Vascular Hypertension 25 9 22 8 Respiratory Cough 20 0.8 19 0.3 Epistaxis 17 1 22 0.3 Renal Proteinuria Based on adverse reaction terms since laboratory data for proteinuria was not systematically collected 16 3 15 3 Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150 Laboratory Abnormality Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin Bevacizumab, Paclitaxel and Carboplatin All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab with bevacizumab, paclitaxel, and carboplatin range: (337–380); bevacizumab, paclitaxel, and carboplatin (range: 337–382). Graded per NCI CTCAE v4.0 Hematology Anemia 83 10 83 9 Neutropenia 52 31 45 26 Lymphopenia 48 17 38 13 Chemistry Hyperglycemia 61 0 60 0 Increased BUN 52 NA NA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities 44 NA Hypomagnesemia 42 2 36 1 Hypoalbuminemia 40 3 31 2 Increased AST 40 4 28 0.8 Hyponatremia 38 10 36 9 Increased Alkaline Phosphatase 37 2 32 1 Increased ALT 37 6 28 0.5 Increased TSH 30 NA 20 NA Hyperkalemia 28 3 25 2 Increased Creatinine 28 1 19 2 Hypocalcemia 26 3 21 3 Hypophosphatemia 25 4 18 4 Hypokalemia 23 7 14 4 Hyperphosphatemia 25 NA 19 NA IMpower130 The safety of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, a multicenter, international, randomized, open-label trial in which 473 chemotherapy-naïve patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m 2 intravenously on Days 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by intravenous atezolizumab 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ] . Among patients receiving intravenous atezolizumab, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. Fatal adverse reactions occurred in 5.3% of patients receiving intravenous atezolizumab; these included pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%), pneumonitis (0.4%) and sepsis, septic shock, staphylococcal sepsis, aspiration, respiratory distress, cardiorespiratory arrest, ventricular tachycardia, death (not otherwise specified), and hepatic cirrhosis (0.2% each). Serious adverse reactions occurred in 51% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (≥ 2%) were pneumonia (6%), diarrhea (3%), lung infection (3%), pulmonary embolism (3%), chronic obstructive pulmonary disease exacerbation (2.5%), dyspnea (2.3%), and febrile neutropenia (1.9%). Intravenous atezolizumab was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia (0.8%), pulmonary embolism (0.8%), fatigue (0.6%), dyspnea (0.6%), pneumonitis (0.6%), neutropenia (0.4%), nausea (0.4%), renal failure (0.4%), cardiac arrest (0.4%), and septic shock (0.4%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 62% of patients; the most common (> 1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia. Tables 11 and 12 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with paclitaxel protein-bound and carboplatin in IMpower130. Table 11: Adverse Reactions Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower130 Adverse Reaction Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473 Paclitaxel Protein-Bound and Carboplatin N = 232 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/Asthenia 61 11 60 8 Gastrointestinal Nausea 50 3.4 46 2.2 Diarrhea Includes diarrhea, colitis, and gastroenteritis 43 6 32 6 Constipation 36 1.1 31 0 Vomiting 27 2.7 19 2.2 Musculoskeletal and Connective Tissue Myalgia/Pain Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 38 3 22 0.4 Nervous System Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 33 2.5 28 2.2 Respiratory, Thoracic and Mediastinal Dyspnea Includes dyspnea, dyspnea exertional and wheezing 32 4.9 25 1.3 Cough 27 0.6 17 0 Skin and Subcutaneous Tissue Alopecia 32 0 27 0 Rash Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular 20 0.6 11 0.9 Metabolism and Nutrition Decreased appetite 30 2.1 26 2.2 Table 12: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower130 Laboratory Abnormality Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473 Paclitaxel Protein-Bound and Carboplatin N = 232 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423–467); paclitaxel protein-bound and carboplatin (range: 218–229). Graded per NCI CTCAE v4.0. Hematology Anemia 92 33 87 25 Neutropenia 75 50 67 39 Thrombocytopenia 73 19 59 13 Lymphopenia 71 23 61 16 Chemistry Hyperglycemia 75 8 66 8 Hypomagnesemia 50 3.4 42 3.2 Hyponatremia 37 9 28 7 Hypoalbuminemia 35 1.3 31 0 Increased ALT 31 2.8 24 3.9 Hypocalcemia 31 2.6 27 1.8 Hypophosphatemia 29 6 20 3.2 Increased AST 28 2.2 24 1.8 Increased TSH 26 NA NA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities 5 NA Hypokalemia 26 6 24 4.4 Increased Alkaline Phosphatase 25 2.6 22 1.3 Increased Blood Creatinine 23 2.8 16 0.4 Hyperphosphatemia 21 NA 13 NA Previously Treated Metastatic NSCLC OAK The safety of intravenous atezolizumab was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.1) ]. A total of 609 patients received intravenous atezolizumab 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n = 578) 75 mg/m 2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The median duration of exposure was 3.4 months (0 to 26 months) in intravenous atezolizumab-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients. The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure. Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (> 1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection. Intravenous atezolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to intravenous atezolizumab discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of intravenous atezolizumab occurred in 25% of patients; the most common (> 1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain. Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in OAK. Table 13: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK Adverse Reaction Intravenous Atezolizumab N = 609 Docetaxel N = 578 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/Asthenia Includes fatigue and asthenia 44 4 53 6 Pyrexia 18 < 1 13 < 1 Respiratory Cough Includes cough and exertional cough 26 < 1 21 < 1 Dyspnea 22 2.8 21 2.6 Metabolism and Nutrition Decreased appetite 23 < 1 24 1.6 Musculoskeletal Myalgia/Pain Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 20 1.3 20 < 1 Arthralgia 12 0.5 10 0.2 Gastrointestinal Nausea 18 < 1 23 < 1 Constipation 18 < 1 14 < 1 Diarrhea 16 < 1 24 2 Skin Rash Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid 12 < 1 10 0 Table 14: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK Laboratory Abnormality Intravenous Atezolizumab Docetaxel All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0 Hematology Anemia 67 3 82 7 Lymphocytopenia 49 14 60 21 Chemistry Hypoalbuminemia 48 4 50 3 Hyponatremia 42 7 31 6 Increased Alkaline Phosphatase 39 2 25 1 Increased AST 31 3 16 0.5 Increased ALT 27 3 14 0.5 Hypophosphatemia 27 5 23 4 Hypomagnesemia 26 1 21 1 Increased Creatinine 23 2 16 1 Adverse Reactions in Adult Patients with Small Cell Lung Cancer The safety of TECENTRIQ HYBREZA for its approved Small Cell Lung Cancer (SCLC) indications [see Indications and Usage (1.2) ] has been established in adequate and well-controlled studies of intravenous atezolizumab for SCLC (IMpower133 and IMforte studies). Small Cell Lung Cancer (SCLC) IMpower133 The safety of intravenous atezolizumab with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received intravenous atezolizumab 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m 2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by intravenous atezolizumab 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2) ]. Among 198 patients receiving intravenous atezolizumab, 32% were exposed for 6 months or longer and 12% were exposed for 12 months or longer. Fatal adverse reactions occurred in 2% of patients receiving intravenous atezolizumab. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each). Serious adverse reactions occurred in 37% of patients receiving intravenous atezolizumab. Serious adverse reactions in > 2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%). Intravenous atezolizumab was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in > 2% of patients was infusion-related reactions (2.5%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 59% of patients; the most common (> 1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%). Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with carboplatin and etoposide in IMpower133. Table 15: Adverse Reactions Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133 Adverse Reaction Intravenous Atezolizumab with Carboplatin and Etoposide N = 198 Placebo with Carboplatin and Etoposide N = 196 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/Asthenia 39 5 33 3 Gastrointestinal Nausea 38 1 33 1 Constipation 26 1 30 1 Vomiting 20 2 17 3 Skin and Subcutaneous Tissue Alopecia 37 0 35 0 Metabolism and Nutrition Decreased appetite 27 1 18 0 Table 16: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133 Laboratory Abnormality Intravenous Atezolizumab with Carboplatin and Etoposide Placebo with Carboplatin and Etoposide All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab (range: 181–193); Placebo (range: 181–196). Graded per NCI CTCAE v4.0 Hematology Anemia 94 17 93 19 Neutropenia 73 45 76 48 Thrombocytopenia 58 20 53 17 Lymphopenia 46 14 38 11 Chemistry Hyperglycemia 67 10 65 8 Increased Alkaline Phosphatase 38 1 35 2 Hyponatremia 34 15 33 11 Hypoalbuminemia 32 1 30 0 Decreased TSH TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. 28 NA NA = Not applicable 15 NA Hypomagnesemia 31 5 35 6 Hypocalcemia 26 3 28 5 Increased ALT 26 3 31 1 Increased AST 22 1 21 2 Increased Blood Creatinine 22 4 15 1 Hyperphosphatemia 21 NA 23 NA Increased TSH 21 NA 7 NA IMforte The safety of intravenous atezolizumab in combination with lurbinectedin was evaluated in IMforte [see Clinical Studies (14.2) ] . Patients received intravenous atezolizumab 1200 mg IV and lurbinectedin 3.2 mg/m 2 IV, on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Primary prophylaxis of G-CSF was administered to 84% of patients. Among 242 patients receiving intravenous atezolizumab with lurbinectedin, the median duration of exposure to intravenous atezolizumab was 4.2 months, with 34% of patients exposed for 6 months or longer and 8% of patients exposed for 12 months or longer. Serious adverse reactions occurred in 31% of patients receiving intravenous atezolizumab with lurbinectedin. Serious adverse reactions in >2% of patients were pneumonia (2.5%), respiratory tract infection (2.1%), dyspnea (2.1%), and decreased platelet count (2.1%). Fatal adverse reactions occurred in 5% of patients receiving intravenous atezolizumab with lurbinectedin including pneumonia (3 patients), sepsis (3 patients), cardio-respiratory arrest (2 patients), myocardial infarction (2 patients), and febrile neutropenia (1 patient). Permanent discontinuation of intravenous atezolizumab due to an adverse reaction occurred in 2.5% of patients. The adverse reactions requiring permanent discontinuation in ≥ 1% of patients who received intravenous atezolizumab were immune-mediated nephritis, peripheral neuropathy, nephropathy, pneumonitis, anemia, neutropenia, and thrombocytopenia. Dosage interruptions of intravenous atezolizumab due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, pneumonitis, and decreased platelet count. Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with lurbinectedin in IMforte. Table 17: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received Intravenous Atezolizumab with Lurbinectedin in IMforte Adverse Reaction Intravenous Atezolizumab with Lurbinectedin N = 242 Intravenous Atezolizumab N = 240 All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Graded per NCI CTCAE v5.0 Gastrointestinal Nausea 36 3 4 1 Diarrhea Includes diarrhea and colitis. 15 0 8 0 Vomiting 14 1 3 0 Constipation 12 0 6 1 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 32 5 13 2 Musculoskeletal and connective tissue disorders Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. 19 2 16 1 Metabolism and Nutrition Decreased appetite 17 0 7 0 Respiratory, thoracic and mediastinal disorders Cough Includes cough, productive cough, and upper-airway cough syndrome. 12 0 8 0 Dyspnea Includes dyspnea and dyspnea exertional. 11 2 10 2 Clinically relevant adverse reactions in < 10% of patients who received intravenous atezolizumab in combination with lurbinectedin included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity and increased creatine phosphokinase. Table 18: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received Intravenous Atezolizumab in Combination with Lurbinectedin in IMforte Laboratory Abnormality Intravenous Atezolizumab with Lurbinectedin N = 242 Intravenous Atezolizumab N = 240 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v5.0 Hematology Lymphopenia 55 17 31 11 Thrombocytopenia 54 15 15 3 Anemia 51 13 12 3 Neutropenia 36 18 7 4 Chemistry Increased alkaline phosphatase 29 1 14 0 Decreased sodium 27 4 30 5 Increased ALT 25 3 18 2 Increased AST 24 3 22 1 Decreased calcium 24 3 8 1 Increased creatinine 21 3 14 0 Adverse Reactions in Adult Patients with Hepatocellular Carcinoma The safety of TECENTRIQ HYBREZA for its approved indication hepatocellular carcinoma [see Indications and Usage (1.3) ] has been established in adequate and well-controlled studies of intravenous atezolizumab for hepatocellular carcinoma (IMbrave150 study). Hepatocellular Carcinoma IMbrave150 The safety of intravenous atezolizumab in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.3) ]. Patients received 1,200 mg of intravenous atezolizumab intravenously followed by 15 mg/kg bevacizumab (n = 329) every 3 weeks, or 400 mg of sorafenib (n = 156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab was 7.4 months (range: 0–16 months) and to bevacizumab was 6.9 months (range: 0–16 months). Fatal adverse reactions occurred in 4.6% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%). Serious adverse reactions occurred in 38% of patients in the intravenous atezolizumab and bevacizumab arm. The most frequent serious adverse reactions (≥ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%). Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 9% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to intravenous atezolizumab discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 41% of patients in the intravenous atezolizumab and bevacizumab arm; the most common (≥ 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatase (8%); infections (6%); gastrointestinal hemorrhages (3.6%); thrombocytopenia/decreased platelet count (3.6%); hyperthyroidism (2.7%); and pyrexia (2.1%). Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the intravenous atezolizumab and bevacizumab arm. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave150. Table 19: Adverse Reactions Occurring in ≥ 10% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150 Adverse Reaction Intravenous Atezolizumab in combination with Bevacizumab (n = 329) Sorafenib (n = 156) All Grades Graded per NCI CTCAE v4.0 (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Vascular Disorders Hypertension 30 15 24 12 General Disorders and Administration Site Conditions Fatigue/Asthenia Includes fatigue and asthenia 26 2 32 6 Pyrexia 18 0 10 0 Renal and Urinary Disorders Proteinuria 20 3 7 0.6 Investigations Weight Decreased 11 0 10 0 Skin and Subcutaneous Tissue Disorders Pruritus 19 0 10 0 Rash 12 0 17 2.6 Gastrointestinal Disorders Diarrhea 19 1.8 49 5 Constipation 13 0 14 0 Abdominal Pain 12 0 17 0 Nausea 12 0 16 0 Vomiting 10 0 8 0 Metabolism and Nutrition Disorders Decreased Appetite 18 1.2 24 3.8 Respiratory, Thoracic and Mediastinal Disorders Cough 12 0 10 0 Epistaxis 10 0 4.5 0 Injury, Poisoning and Procedural Complications Infusion-Related Reaction 11 2.4 0 0 Table 20: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150 Laboratory Abnormality Intravenous Atezolizumab in combination with Bevacizumab (n = 329) Sorafenib (n = 156) All Grades Graded per NCI CTCAE v4.0 (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153) Chemistry Increased AST 86 16 90 16 Increased Alkaline Phosphatase 70 4 76 4.6 Increased ALT 62 8 70 4.6 Decreased Albumin 60 1.5 54 0.7 Decreased Sodium 54 13 49 9 Increased Glucose 48 9 43 4.6 Decreased Calcium 30 0.3 35 1.3 Decreased Phosphorus 26 4.7 58 16 Increased Potassium 23 1.9 16 2 Hypomagnesemia 22 0 22 0 Hematology Decreased Platelet 68 7 63 4.6 Decreased Lymphocytes 62 13 58 11 Decreased Hemoglobin 58 3.1 62 3.9 Increased Bilirubin 57 8 59 14 Decreased Leukocyte 32 3.4 29 1.3 Decreased Neutrophil 23 2.3 16 1.1 Adverse Reactions in Adult Patients with Melanoma The safety of TECENTRIQ HYBREZA for its approved melanoma indication [see Indications and Usage (1.4) ] has been established in adequate and well-controlled studies of intravenous atezolizumab for melanoma (IMspire150 study). Metastatic Melanoma IMspire150 The safety of intravenous atezolizumab, administered with cobimetinib and vemurafenib, was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.4) ] . Patients received intravenous atezolizumab with cobimetinib and vemurafenib (n = 230) or placebo with cobimetinib and vemurafenib (n = 281). Among the 230 patients who received intravenous atezolizumab administered with cobimetinib and vemurafenib, the median duration of exposure to intravenous atezolizumab was 9.2 months (range: 0–30 months), to cobimetinib was 10.0 months (range: 1–31 months) and to vemurafenib was 9.8 months (range: 1–31 months). Fatal adverse reactions occurred in 3% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest. Serious adverse reactions occurred in 45% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) serious adverse reactions were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%). Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 21% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to intravenous atezolizumab discontinuation were increased ALT (2.2%) and pneumonitis (2.6%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 68% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to intravenous atezolizumab interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%). Tables 21 and 22 summarize the incidence of adverse reactions and laboratory abnormalities in IMspire150. Table 21: Adverse Reactions Occurring in ≥ 10% of Patients on the Intravenous Atezolizumab plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 Intravenous Atezolizumab in IMspire150) Adverse Reaction Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230) Placebo with Cobimetinib and Vemurafenib (n=281) All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Skin and Subcutaneous Tissue Disorders Rash Includes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized and rash morbilliform 75 27 72 23 Pruritus 26 < 1 17 < 1 Photosensitivity reaction 21 < 1 25 3.2 General Disorders and Administration Site Conditions Fatigue Includes fatigue, asthenia and malaise 51 3 45 1.8 Pyrexia Includes pyrexia and hyperpyrexia 49 1.7 35 2.1 Edema Includes edema peripheral, lymphoedema, edema, face edema, eyelid edema, periorbital edema, lip edema and generalized edema 26 < 1 21 0 Gastrointestinal Disorders Hepatotoxicity Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 50 21 36 13 Nausea 30 < 1 32 2.5 Stomatitis Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 23 1.3 15 < 1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain 62 4.3 48 3.2 Endocrine Disorders Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 22 0 10 0 Hyperthyroidism 18 < 1 8 0 Injury, Poisoning and Procedural Complications Infusion-related reaction Includes infusion related reaction and hypersensitivity 10 2.6 8 < 1 Respiratory, Thoracic and Mediastinal Disorders Pneumonitis Includes pneumonitis and interstitial lung disease 12 1.3 6 < 1 Vascular Disorders Hypertension Includes hypertension, blood pressure increased, hypertensive crisis 17 10 18 7 Clinically important adverse reactions in < 10% of patients who received intravenous atezolizumab plus cobimetinib and vemurafenib were: Cardiac Disorders : Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged Eye Disorders : Uveitis Gastrointestinal disorders : Pancreatitis Infections and infestations: Pneumonia, urinary tract infection Metabolism and nutrition disorders: Hyperglycemia Nervous system Disorders : Dizziness, dysgeusia, syncope Respiratory, thoracic and mediastinal disorders : Dyspnea, oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Vitiligo Table 22: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3–4) in IMspire150 Laboratory Abnormality Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230) Placebo with Cobimetinib and Vemurafenib (n=281) All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230). Hematology Decreased Lymphocytes 80 24 72 17 Decreased Hemoglobin 77 2.6 72 2.2 Decreased Platelet 34 1.3 24 0.4 Decreased Neutrophils 26 2.2 19 1.5 Chemistry Increased Creatine Kinase 88 22 81 18 Increased AST 80 13 68 6 Increased ALT 79 18 62 12 Increased Triacylglycerol Lipase 75 46 62 35 Increased Alkaline Phosphatase 73 6 63 2.9 Decreased Phosphorus 67 22 64 14 Increased Amylase 51 13 45 13 Increased Blood Urea Nitrogen 47 NA NA = Not applicable. NCI CTCAE v4.0 does not include these laboratories 37 NA Decreased Albumin 43 0.9 34 1.5 Increased Bilirubin 42 3.1 33 0.7 Decreased Calcium 41 1.3 28 0 Decreased Sodium 40 5 34 7 Decreased Thyroid-Stimulating Hormone 38 NA 23 NA Increased Thyroid-Stimulating Hormone Increased Thyroid Stimulating Hormone has a difference < 5% (All Grades) between arms and is included for clinical completeness 37 NA 33 NA Decreased Potassium 36 5 22 4.3 Increased Triiodothyronine 33 NA 18 NA Increased Free Thyroxine 32 NA 21 NA Decreased Total Triiodothyronine 32 NA 8 NA Increased Potassium 29 1.3 19 1.4 Decreased Triiodothyronine 27 NA 21 NA Increased Sodium 20 0 13 0.4 Adverse Reactions in Adults with Alveolar Soft Part Sarcoma The safety of TECENTRIQ HYBREZA for its approved alveolar soft part sarcoma (ASPS) indication [see Indications and Usage (1.5) ] has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS (ML39345 study). Alveolar Soft Part Sarcoma ML39345 Study The safety of intravenous atezolizumab was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5) ]. Adult patients received intravenous atezolizumab 1200 mg every 3 weeks and pediatric patients received 15 mg/kg up to a maximum 1200 mg every 3 weeks until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab was 8.9 months (1 to 40 months). Serious adverse reactions occurred in 41% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each). Dosage interruptions of intravenous atezolizumab due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (≥ 3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each). Tables 23 and 24 summarize adverse reactions and laboratory abnormalities in Study ML39345. Table 23: Adverse Reactions Occurring in ≥ 15% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345 Adverse Reaction Intravenous Atezolizumab N = 49 All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General disorders and administration site conditions Fatigue 55 2 Pyrexia 25 2 Influenza like illness 18 0 Gastrointestinal disorders Nausea 43 0 Vomiting 37 0 Constipation 33 0 Diarrhea 27 2 Abdominal pain Includes abdominal pain and abdominal pain upper 25 0 Metabolism and nutrition disorders Decreased appetite 22 2 Respiratory, Thoracic and Mediastinal Cough Includes cough, upper-airway cough syndrome, and productive cough 45 0 Dyspnea 33 0 Rhinitis allergic 16 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain 67 8 Skin and subcutaneous tissue disorders Rash Includes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption 47 2 Nervous system disorders Headache 43 4 Dizziness Includes vertigo and dizziness 29 4 Vascular disorders Hypertension 43 6 Hemorrhage Includes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage 29 2 Psychiatric disorders Insomnia 27 0 Anxiety 25 0 Cardiac Disorders Arrhythmia Includes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia 22 2 Endocrine disorders Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 25 0 Investigations Weight decreased 18 0 Weight increased 16 6 Table 24: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345 Laboratory Abnormality Laboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges Intravenous Atezolizumab The denominators used to calculate the rate varied from 4–49 for all tests of interest based on the number of patients with a baseline value and at least one on-study laboratory measurement available All Grades (%) Grades 3–4 (%) Hematology Decreased Hemoglobin 63 0 Decreased Platelets 27 0 Increased Platelets 29 0 Chemistry Increased Alkaline Phosphatase 29 0 Decreased Amylase 40 0 Increased Amylase 20 20 Decreased Bilirubin 49 0 Decreased Calcium 47 0 Increased Calcium 25 14 Decreased Glucose 33 0 Increased Glucose 78 0 Decreased Glucose (fasting) 25 0 Decreased Magnesium 21 0 Increased Magnesium 26 26 Increased AST 39 2 Increased ALT 33 2 Decreased Sodium 43 0 Increased Lipase 25 25 Adverse Reactions in Adult Patients with Muscle Invasive Bladder Cancer The safety of TECENTRIQ HYBREZA for its approved muscle invasive bladder cancer (MIBC) indication [see Indications and Usage (1.6) ] has been established in an adequate and well-controlled study of intravenous atezolizumab for MIBC (IMvigor011 study). Muscle Invasive Bladder Cancer IMvigor011 The safety of intravenous atezolizumab was evaluated in IMvigor011, a multi-center, randomized, double-blind, placebo-controlled trial in 248 patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD) [see Clinical Studies (14.6) ] . Patients received intravenous atezolizumab 1680 mg (n=165) or placebo (n=83) every 4 weeks for up to 12 cycles or 1 year (whichever occurred first) unless either unacceptable toxicity or disease recurrence occurred. The median duration of exposure to intravenous atezolizumab was 6.5 months (0 to 11.8 months). Serious adverse reactions occurred in 27% of patients who received intravenous atezolizumab. Serious adverse reactions in ≥ 2% of patients included urinary tract infection (9%), and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3% of patients who received intravenous atezolizumab including septic shock, skin infection, death of unknown cause, interstitial lung disease, and congestive cardiac failure (1 patient each). Permanent discontinuation of intravenous atezolizumab due to adverse reactions occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous atezolizumab in ≥1% of patients included pneumonitis (1.8%). Dosage interruptions of intravenous atezolizumab due to adverse reactions occurred in 24% of patients. Adverse reactions which required dosage interruptions in ≥1% of patients included urinary tract infection (4.8%), COVID-19 (3.6%), increased blood creatinine, atrial fibrillation, abnormal hepatic function, pneumonitis, rash, hyperthyroidism, and hypothyroidism (1.2% each). Tables 25 and 26 summarize the adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab in IMvigor011. Table 25: Adverse Reactions Occurring in ≥10% of Patients with MIBC Who Received Intravenous Atezolizumab [at a Higher Incidence (Between Arm Difference of ≥2%) Compared to Placebo] in IMvigor011 Adverse Reaction Graded per NCI-CTCAE v5.0 Intravenous Atezolizumab N = 165 Placebo N=83 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Renal and Urinary Disorders Urinary tract infection Includes multiple related terms 22 8.5 18 4.8 Skin and Subcutaneous Tissue Pruritus 18 0 11 0 Rash 13 0.6 3.6 0 Endocrine Disorders Hypothyroidism 13 0 4.8 0 Gastrointestinal Constipation 11 0 7 0 Table 26 Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with MIBC Who Received Intravenous Atezolizumab [at a Higher Incidence (Between Arm Difference of ≥2%) Compared to Placebo] in IMvigor011 Laboratory Abnormality Intravenous Atezolizumab N=165 Placebo N=83 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI-CTCAE v5.0 Denominator is based on patients with at least one post-baseline assessment. For each parameter, the denominator includes patients with baseline Grade 0-2 in the specified direction of abnormality or patients with missing baseline values Hematology Decreased hemoglobin 30 1.8 24 0 Decreased lymphocytes 26 3.1 15 0 Chemistry Increased alanine aminotransferase 23 2.5 10 0 Increased alkaline phosphatase 23 1.2 15 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of intravenous atezolizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: pericarditis, pericardial effusion, cardiac tamponade Musculoskeletal and Connective Tissue: tenosynovitis" ], "adverse_reactions_table": [ "
Table 3: Adverse Reactions (≥ 10%) in Adult Patients with Locally Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001
Adverse ReactionGraded per NCI CTCAE v5.0TECENTRIQ HYBREZA n = 247Intravenous Atezolizumab n = 124
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
General Disorder and Administration Site Conditions
FatigueComposite term includes fatigue, asthenia190.8180
Musculoskeletal and Connective Tissue disorders
Musculoskeletal PainComposite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain150.4133.2
Respiratory, Thoracic and Mediastinal
CoughComposite term includes cough, productive cough13070
DyspneaComposite term includes dyspnea, dyspnea at rest, dyspnea exertional121.2151.6
Metabolism and Nutrition Disorders
Decreased appetite110110
", "
Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001
Laboratory AbnormalityGraded per NCI CTCAE v5.0TECENTRIQ HYBREZA (n = 247)Intravenous Atezolizumab (n = 124)
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ HYBREZA (48-233) and intravenous atezolizumab (19-117)
Hematology
Decreased Hemoglobin 676635
Decreased lymphocytes3794515
Chemistry
Decreased Sodium463.9475
Decreased Albumin342.2270
Increased Alkaline Phosphatase331.3270
Increased AST282.6322.6
Increased ALT282.6231.7
Decreased calcium222.6230.9
Increased calcium202.6241.7
Increased potassium211.7221.7
Increased INR202230
Increased Creatinine191.7260.9
", "
Table 5: Adverse Reactions Occurring in ≥ 10% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010
Adverse ReactionGraded per NCI CTCAE v4.0Intravenous Atezolizumab N = 495Best Supportive Care N = 495
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Skin and Subcutaneous Tissue
RashIncludes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform171.21.40
Pruritus1000.60
Endocrine Disorders
HypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased1400.60
Respiratory, Thoracic and Mediastinal
CoughProductive cough, upper airway cough syndrome, cough160110
General
PyrexiaIncludes pyrexia, body temperature increased, hyperthermia140.82.20.2
FatigueIncludes fatigue, asthenia140.650.2
Nervous System Disorders
Peripheral neuropathyIncludes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy120.470.2
Musculoskeletal and Connective Tissue
Musculoskeletal painIncludes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain140.890.2
ArthralgiaIncludes arthralgia, arthritis110.660
", "
Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010
Laboratory AbnormalityGraded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0).Intravenous AtezolizumabThe denominators used to calculate the rate varied from 78–480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value.Best Supportive Care
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Chemistry
Increased aspartate aminotransferase342.5180
Increased alanine aminotransferase303.3190.4
Hyperkalemia243.5152.5
Increased blood creatinine310.2230.2
", "
Table 7: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower110
Adverse ReactionIntravenous Atezolizumab N = 286Platinum-Based Chemotherapy N = 263
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
Gastrointestinal
Nausea140.3341.9
Constipation121.0220.8
Diarrhea110120.8
General
Fatigue/Asthenia251.4344.2
Pyrexia14090.4
Metabolism and Nutrition
Decreased appetite150.7190
Respiratory, Thoracic and Mediastinal
Dyspnea140.7100
Cough120.3100
", "
Table 8: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower110
Laboratory AbnormalityIntravenous AtezolizumabPlatinum-Based Chemotherapy
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: intravenous atezolizumab (range: 278–281); platinum-based chemotherapy (range: 256–260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.
Hematology
Anemia691.89420
Lymphopenia4795917
Chemistry
Hypoalbuminemia480.4392
Increased alkaline phosphatase462.5421.2
Hyponatremia449367
Increased ALT383.2320.8
Increased AST363.2320.8
Hyperkalemia293.9362.7
Hypocalcemia241.4242.7
Increased blood creatinine240.7331.5
Hypophosphatemia233.6212
", "
Table 9: Adverse Reactions Occurring in ≥ 15% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150
Adverse ReactionIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin N = 393Bevacizumab, Paclitaxel and Carboplatin N = 394
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
Nervous System
NeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy563473
Headache160.8130
General
Fatigue/Asthenia506466
Pyrexia190.390.5
Skin and Subcutaneous Tissue
Alopecia480460
RashIncludes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform232100.3
Musculoskeletal and Connective Tissue
Myalgia/PainIncludes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain423342
Arthralgia261221
Gastrointestinal
Nausea394322
DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis336250.5
Constipation300.3230.3
Vomiting192181
Metabolism and Nutrition
Decreased appetite294210.8
Vascular
Hypertension259228
Respiratory
Cough200.8190.3
Epistaxis171220.3
Renal
ProteinuriaBased on adverse reaction terms since laboratory data for proteinuria was not systematically collected163153
", "
Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150
Laboratory AbnormalityIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and CarboplatinBevacizumab, Paclitaxel and Carboplatin
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab with bevacizumab, paclitaxel, and carboplatin range: (337–380); bevacizumab, paclitaxel, and carboplatin (range: 337–382). Graded per NCI CTCAE v4.0
Hematology
Anemia8310839
Neutropenia52314526
Lymphopenia48173813
Chemistry
Hyperglycemia610600
Increased BUN 52NANA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities44NA
Hypomagnesemia422361
Hypoalbuminemia403312
Increased AST404280.8
Hyponatremia3810369
Increased Alkaline Phosphatase372321
Increased ALT376280.5
Increased TSH30NA20NA
Hyperkalemia283252
Increased Creatinine281192
Hypocalcemia263213
Hypophosphatemia254184
Hypokalemia237144
Hyperphosphatemia25NA19NA
", "
Table 11: Adverse Reactions Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower130
Adverse ReactionIntravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473Paclitaxel Protein-Bound and Carboplatin N = 232
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General
Fatigue/Asthenia6111608
Gastrointestinal
Nausea503.4462.2
DiarrheaIncludes diarrhea, colitis, and gastroenteritis436326
Constipation361.1310
Vomiting272.7192.2
Musculoskeletal and Connective Tissue
Myalgia/PainIncludes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort383220.4
Nervous System
NeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy332.5282.2
Respiratory, Thoracic and Mediastinal
DyspneaIncludes dyspnea, dyspnea exertional and wheezing324.9251.3
Cough270.6170
Skin and Subcutaneous Tissue
Alopecia320270
RashIncludes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular200.6110.9
Metabolism and Nutrition
Decreased appetite302.1262.2
", "
Table 12: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower130
Laboratory AbnormalityIntravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473Paclitaxel Protein-Bound and Carboplatin N = 232
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423–467); paclitaxel protein-bound and carboplatin (range: 218–229). Graded per NCI CTCAE v4.0.
Hematology
Anemia92338725
Neutropenia75506739
Thrombocytopenia73195913
Lymphopenia71236116
Chemistry
Hyperglycemia758668
Hypomagnesemia503.4423.2
Hyponatremia379287
Hypoalbuminemia351.3310
Increased ALT312.8243.9
Hypocalcemia312.6271.8
Hypophosphatemia296203.2
Increased AST282.2241.8
Increased TSH26NANA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities5NA
Hypokalemia266244.4
Increased Alkaline Phosphatase252.6221.3
Increased Blood Creatinine232.8160.4
Hyperphosphatemia21NA13NA
", "
Table 13: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK
Adverse ReactionIntravenous Atezolizumab N = 609Docetaxel N = 578
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General
Fatigue/AstheniaIncludes fatigue and asthenia444536
Pyrexia18< 113< 1
Respiratory
CoughIncludes cough and exertional cough26< 121< 1
Dyspnea222.8212.6
Metabolism and Nutrition
Decreased appetite23< 1241.6
Musculoskeletal
Myalgia/PainIncludes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia201.320< 1
Arthralgia120.5100.2
Gastrointestinal
Nausea18< 123< 1
Constipation18< 114< 1
Diarrhea16< 1242
Skin
RashIncludes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid12< 1100
", "
Table 14: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK
Laboratory AbnormalityIntravenous AtezolizumabDocetaxel
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0
Hematology
Anemia673827
Lymphocytopenia49146021
Chemistry
Hypoalbuminemia484503
Hyponatremia427316
Increased Alkaline Phosphatase392251
Increased AST313160.5
Increased ALT273140.5
Hypophosphatemia275234
Hypomagnesemia261211
Increased Creatinine232161
", "
Table 15: Adverse Reactions Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133
Adverse ReactionIntravenous Atezolizumab with Carboplatin and Etoposide N = 198Placebo with Carboplatin and Etoposide N = 196
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General
Fatigue/Asthenia395333
Gastrointestinal
Nausea381331
Constipation261301
Vomiting202173
Skin and Subcutaneous Tissue
Alopecia370350
Metabolism and Nutrition
Decreased appetite271180
", "
Table 16: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133
Laboratory AbnormalityIntravenous Atezolizumab with Carboplatin and EtoposidePlacebo with Carboplatin and Etoposide
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab (range: 181–193); Placebo (range: 181–196). Graded per NCI CTCAE v4.0
Hematology
Anemia94179319
Neutropenia73457648
Thrombocytopenia58205317
Lymphopenia46143811
Chemistry
Hyperglycemia6710658
Increased Alkaline Phosphatase381352
Hyponatremia34153311
Hypoalbuminemia321300
Decreased TSHTSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories.28NANA = Not applicable15NA
Hypomagnesemia315356
Hypocalcemia263285
Increased ALT263311
Increased AST221212
Increased Blood Creatinine224151
Hyperphosphatemia21NA23NA
Increased TSH21NA7NA
", "
Table 17: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received Intravenous Atezolizumab with Lurbinectedin in IMforte
Adverse ReactionIntravenous Atezolizumab with Lurbinectedin N = 242Intravenous Atezolizumab N = 240
All Grades (%)Grades 3 or 4 (%)All Grades (%)Grades 3 or 4 (%)
Graded per NCI CTCAE v5.0
Gastrointestinal
Nausea36341
DiarrheaIncludes diarrhea and colitis.15080
Vomiting14130
Constipation12061
General disorders and administration site conditions
FatigueIncludes fatigue and asthenia.325132
Musculoskeletal and connective tissue disorders
Musculoskeletal PainIncludes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity.192161
Metabolism and Nutrition
Decreased appetite17070
Respiratory, thoracic and mediastinal disorders
CoughIncludes cough, productive cough, and upper-airway cough syndrome.12080
DyspneaIncludes dyspnea and dyspnea exertional.112102
", "
Table 18: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received Intravenous Atezolizumab in Combination with Lurbinectedin in IMforte
Laboratory AbnormalityIntravenous Atezolizumab with Lurbinectedin N = 242Intravenous Atezolizumab N = 240
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v5.0
Hematology
Lymphopenia 55173111
Thrombocytopenia5415153
Anemia5113123
Neutropenia361874
Chemistry
Increased alkaline phosphatase 291140
Decreased sodium 274305
Increased ALT253182
Increased AST243221
Decreased calcium24381
Increased creatinine213140
", "
Table 19: Adverse Reactions Occurring in ≥ 10% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150
Adverse ReactionIntravenous Atezolizumab in combination with Bevacizumab (n = 329)Sorafenib (n = 156)
All GradesGraded per NCI CTCAE v4.0 (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Vascular Disorders
Hypertension30152412
General Disorders and Administration Site Conditions
Fatigue/AstheniaIncludes fatigue and asthenia262326
Pyrexia180100
Renal and Urinary Disorders
Proteinuria20370.6
Investigations
Weight Decreased110100
Skin and Subcutaneous Tissue Disorders
Pruritus190100
Rash120172.6
Gastrointestinal Disorders
Diarrhea191.8495
Constipation130140
Abdominal Pain120170
Nausea120160
Vomiting10080
Metabolism and Nutrition Disorders
Decreased Appetite181.2243.8
Respiratory, Thoracic and Mediastinal Disorders
Cough120100
Epistaxis1004.50
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction112.400
", "
Table 20: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150
Laboratory AbnormalityIntravenous Atezolizumab in combination with Bevacizumab (n = 329)Sorafenib (n = 156)
All GradesGraded per NCI CTCAE v4.0 (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153)
Chemistry
Increased AST86169016
Increased Alkaline Phosphatase704764.6
Increased ALT628704.6
Decreased Albumin601.5540.7
Decreased Sodium5413499
Increased Glucose489434.6
Decreased Calcium300.3351.3
Decreased Phosphorus264.75816
Increased Potassium231.9162
Hypomagnesemia220220
Hematology
Decreased Platelet687634.6
Decreased Lymphocytes62135811
Decreased Hemoglobin583.1623.9
Increased Bilirubin5785914
Decreased Leukocyte323.4291.3
Decreased Neutrophil232.3161.1
", "
Table 21: Adverse Reactions Occurring in ≥ 10% of Patients on the Intravenous Atezolizumab plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 Intravenous Atezolizumab in IMspire150)
Adverse ReactionIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230)Placebo with Cobimetinib and Vemurafenib (n=281)
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Skin and Subcutaneous Tissue Disorders
RashIncludes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized and rash morbilliform75277223
Pruritus26< 117< 1
Photosensitivity reaction21< 1253.2
General Disorders and Administration Site Conditions
FatigueIncludes fatigue, asthenia and malaise513451.8
PyrexiaIncludes pyrexia and hyperpyrexia491.7352.1
EdemaIncludes edema peripheral, lymphoedema, edema, face edema, eyelid edema, periorbital edema, lip edema and generalized edema26< 1210
Gastrointestinal Disorders
HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal50213613
Nausea30< 1322.5
StomatitisIncludes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis231.315< 1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painIncludes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain624.3483.2
Endocrine Disorders
HypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased220100
Hyperthyroidism18< 180
Injury, Poisoning and Procedural Complications
Infusion-related reactionIncludes infusion related reaction and hypersensitivity102.68< 1
Respiratory, Thoracic and Mediastinal Disorders
PneumonitisIncludes pneumonitis and interstitial lung disease121.36< 1
Vascular Disorders
HypertensionIncludes hypertension, blood pressure increased, hypertensive crisis1710187
", "
Table 22: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3–4) in IMspire150
Laboratory AbnormalityIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230)Placebo with Cobimetinib and Vemurafenib (n=281)
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230).
Hematology
Decreased Lymphocytes80247217
Decreased Hemoglobin772.6722.2
Decreased Platelet341.3240.4
Decreased Neutrophils262.2191.5
Chemistry
Increased Creatine Kinase88228118
Increased AST8013686
Increased ALT79186212
Increased Triacylglycerol Lipase75466235
Increased Alkaline Phosphatase736632.9
Decreased Phosphorus67226414
Increased Amylase51134513
Increased Blood Urea Nitrogen47NANA = Not applicable. NCI CTCAE v4.0 does not include these laboratories37NA
Decreased Albumin430.9341.5
Increased Bilirubin423.1330.7
Decreased Calcium411.3280
Decreased Sodium405347
Decreased Thyroid-Stimulating Hormone38NA23NA
Increased Thyroid-Stimulating HormoneIncreased Thyroid Stimulating Hormone has a difference < 5% (All Grades) between arms and is included for clinical completeness37NA33NA
Decreased Potassium365224.3
Increased Triiodothyronine33NA18NA
Increased Free Thyroxine32NA21NA
Decreased Total Triiodothyronine32NA8NA
Increased Potassium291.3191.4
Decreased Triiodothyronine27NA21NA
Increased Sodium200130.4
", "
Table 23: Adverse Reactions Occurring in ≥ 15% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345
Adverse ReactionIntravenous Atezolizumab N = 49
All Grades (%)Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General disorders and administration site conditions
Fatigue552
Pyrexia252
Influenza like illness180
Gastrointestinal disorders
Nausea430
Vomiting370
Constipation330
Diarrhea272
Abdominal painIncludes abdominal pain and abdominal pain upper250
Metabolism and nutrition disorders
Decreased appetite222
Respiratory, Thoracic and Mediastinal
CoughIncludes cough, upper-airway cough syndrome, and productive cough450
Dyspnea330
Rhinitis allergic160
Musculoskeletal and connective tissue disorders
Musculoskeletal painIncludes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain678
Skin and subcutaneous tissue disorders
RashIncludes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption472
Nervous system disorders
Headache434
DizzinessIncludes vertigo and dizziness294
Vascular disorders
Hypertension436
HemorrhageIncludes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage292
Psychiatric disorders
Insomnia270
Anxiety250
Cardiac Disorders
ArrhythmiaIncludes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia222
Endocrine disorders
HypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased250
Investigations
Weight decreased180
Weight increased166
", "
Table 24: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345
Laboratory AbnormalityLaboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal rangesIntravenous AtezolizumabThe denominators used to calculate the rate varied from 4–49 for all tests of interest based on the number of patients with a baseline value and at least one on-study laboratory measurement available
All Grades (%)Grades 3–4 (%)
Hematology
Decreased Hemoglobin 630
Decreased Platelets270
Increased Platelets290
Chemistry
Increased Alkaline Phosphatase290
Decreased Amylase400
Increased Amylase2020
Decreased Bilirubin490
Decreased Calcium470
Increased Calcium2514
Decreased Glucose 330
Increased Glucose780
Decreased Glucose (fasting)250
Decreased Magnesium210
Increased Magnesium2626
Increased AST392
Increased ALT332
Decreased Sodium430
Increased Lipase2525
", "
Table 25: Adverse Reactions Occurring in ≥10% of Patients with MIBC Who Received Intravenous Atezolizumab [at a Higher Incidence (Between Arm Difference of ≥2%) Compared to Placebo] in IMvigor011
Adverse ReactionGraded per NCI-CTCAE v5.0Intravenous Atezolizumab N = 165Placebo N=83
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Renal and Urinary Disorders
Urinary tract infectionIncludes multiple related terms228.5184.8
Skin and Subcutaneous Tissue
Pruritus180110
Rash130.63.60
Endocrine Disorders
Hypothyroidism1304.80
Gastrointestinal
Constipation 11070
", "
Table 26 Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with MIBC Who Received Intravenous Atezolizumab [at a Higher Incidence (Between Arm Difference of ≥2%) Compared to Placebo] in IMvigor011
Laboratory AbnormalityIntravenous Atezolizumab N=165Placebo N=83
All Grades (%)Grades 3–4 (%)All Grades (%)Grades 3–4 (%)
Graded per NCI-CTCAE v5.0 Denominator is based on patients with at least one post-baseline assessment. For each parameter, the denominator includes patients with baseline Grade 0-2 in the specified direction of abnormality or patients with missing baseline values
Hematology
Decreased hemoglobin301.8240
Decreased lymphocytes263.1150
Chemistry
Increased alanine aminotransferase232.5100
Increased alkaline phosphatase231.2150
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] , TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman . There are no available data on the use of TECENTRIQ HYBREZA in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data ) . Advise females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.4) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase [see Description (11) ] . Atezolizumab : Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Hyaluronidase : In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 2,400 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 400 times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,200 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring. 8.2 Lactation Risk Summary There is no information regarding the presence of atezolizumab or hyaluronidase in human milk or its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to TECENTRIQ HYBREZA are unknown. Because of the potential for serious adverse reactions in breastfed children from TECENTRIQ HYBREZA, advise women not to breastfeed during treatment with TECENTRIQ HYBREZA and for 5 months after the last dose. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ HYBREZA [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1) ] . Contraception Females: Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for 5 months following the last dose. Infertility Females: Based on animal studies, TECENTRIQ HYBREZA may impair fertility in females of reproductive potential while receiving TECENTRIQ HYBREZA treatment [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Alveolar Soft Part Sarcoma The safety and effectiveness of TECENTRIQ HYBREZA as monotherapy for the treatment of pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established. Use of TECENTRIQ HYBREZA for this pediatric indication is supported by evidence from adequate and well controlled studies of intravenous atezolizumab in adults, and additional pharmacokinetic and safety data for intravenous atezolizumab in pediatric patients 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Atezolizumab exposures following subcutaneous administration of TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab) every 3 weeks in pediatric patients 12 years of age and older who weigh 40 kg or greater are predicted to be within the range of those observed in adults at the same dosage. The safety and effectiveness of TECENTRIQ HYBREZA have not been established in pediatric patients <12 years of age with unresectable or metastatic ASPS. Solid Tumors and Lymphomas The safety and effectiveness of TECENTRIQ HYBREZA in pediatric patients have not been established for other approved indications. 8.5 Geriatric Use TECENTRIQ HYBREZA as a Single-Agent Of 247 adult patients treated with TECENTRIQ HYBREZA as monotherapy in IMscin001, 45% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness of TECENTRIQ HYBREZA have been observed between patients aged 65 years or older and younger adult patients. The safety of TECENTRIQ HYBREZA as monotherapy or in combination with other antineoplastic drugs for its approved indications [see Indications and Usage (1.1 , 1.2 , 1.3 , 1.4 , 1.5 , 1.6) ] has been established in adequate and well-controlled studies of intravenous atezolizumab as a single agent and in combination with other antineoplastic drugs. Below is a description of geriatric use information from the intravenous atezolizumab studies. Intravenous Atezolizumab as a Single-Agent Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over. Of the 167 patients with MIBC treated with intravenous atezolizumab in IMvigor011, 117 (70%) patients were 65 years of age and older and 44 (26%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger patients. Intravenous Atezolizumab in Combination with Other Antineoplastic Drugs Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger adult patients. Intravenous Atezolizumab in Combination with Lurbinectedin Of 242 adult patients with ES-SCLC treated with intravenous atezolizumab in combination with lurbinectedin in IMforte, 124 (51%) patients were 65 years of age and older, while 29 (12%) patients were 75 years of age and older. No overall differences in effectiveness were observed between older and younger patients. There was a higher incidence of Grade 3 or 4 adverse reactions (45% vs 31%) and treatment discontinuation (11% vs 0.8%) in patients ≥ 65 years of age compared to younger patients, respectively." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] , TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman . There are no available data on the use of TECENTRIQ HYBREZA in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data ) . Advise females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.4) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase [see Description (11) ] . Atezolizumab : Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Hyaluronidase : In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 2,400 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 400 times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,200 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring." ], "pediatric_use": [ "8.4 Pediatric Use Alveolar Soft Part Sarcoma The safety and effectiveness of TECENTRIQ HYBREZA as monotherapy for the treatment of pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established. Use of TECENTRIQ HYBREZA for this pediatric indication is supported by evidence from adequate and well controlled studies of intravenous atezolizumab in adults, and additional pharmacokinetic and safety data for intravenous atezolizumab in pediatric patients 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Atezolizumab exposures following subcutaneous administration of TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab) every 3 weeks in pediatric patients 12 years of age and older who weigh 40 kg or greater are predicted to be within the range of those observed in adults at the same dosage. The safety and effectiveness of TECENTRIQ HYBREZA have not been established in pediatric patients <12 years of age with unresectable or metastatic ASPS. Solid Tumors and Lymphomas The safety and effectiveness of TECENTRIQ HYBREZA in pediatric patients have not been established for other approved indications." ], "geriatric_use": [ "8.5 Geriatric Use TECENTRIQ HYBREZA as a Single-Agent Of 247 adult patients treated with TECENTRIQ HYBREZA as monotherapy in IMscin001, 45% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness of TECENTRIQ HYBREZA have been observed between patients aged 65 years or older and younger adult patients. The safety of TECENTRIQ HYBREZA as monotherapy or in combination with other antineoplastic drugs for its approved indications [see Indications and Usage (1.1 , 1.2 , 1.3 , 1.4 , 1.5 , 1.6) ] has been established in adequate and well-controlled studies of intravenous atezolizumab as a single agent and in combination with other antineoplastic drugs. Below is a description of geriatric use information from the intravenous atezolizumab studies. Intravenous Atezolizumab as a Single-Agent Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over. Of the 167 patients with MIBC treated with intravenous atezolizumab in IMvigor011, 117 (70%) patients were 65 years of age and older and 44 (26%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger patients. Intravenous Atezolizumab in Combination with Other Antineoplastic Drugs Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger adult patients. Intravenous Atezolizumab in Combination with Lurbinectedin Of 242 adult patients with ES-SCLC treated with intravenous atezolizumab in combination with lurbinectedin in IMforte, 124 (51%) patients were 65 years of age and older, while 29 (12%) patients were 75 years of age and older. No overall differences in effectiveness were observed between older and younger patients. There was a higher incidence of Grade 3 or 4 adverse reactions (45% vs 31%) and treatment discontinuation (11% vs 0.8%) in patients ≥ 65 years of age compared to younger patients, respectively." ], "description": [ "11 DESCRIPTION TECENTRIQ HYBREZA is a fixed-combination drug product containing atezolizumab and hyaluronidase (human recombinant). Atezolizumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa. Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs administered subcutaneously. It is a glycosylated single-chain protein produced by mammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has a molecular weight of approximately 61 kDa. TECENTRIQ HYBREZA (atezolizumab and hyaluronidase-tqjs) injection for subcutaneous use is a sterile, preservative-free, clear and slightly opalescent, and colorless to slightly yellow solution in single-dose vials. Each 15 mL single-dose vial contains 1,875 mg of atezolizumab, 30,000 units of hyaluronidase, histidine (46.5 mg), methionine (22.4 mg), polysorbate 20 (9 mg), sucrose (1,232 mg), and water for injection, adjusted to pH 5.8 with acetic acid." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action PD-L1 may be expressed on tumor cells and/or tumor infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth. In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in TECENTRIQ HYBREZA acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of atezolizumab and hyaluronidase have not been fully characterized. 12.3 Pharmacokinetics When comparing atezolizumab exposure following subcutaneous TECENTRIQ HYBREZA to that of intravenous atezolizumab in Study IMscin001 [see Clinical Studies (14.1) ], the geometric mean ratio (GMR) (90% CI) for Cycle 1 C trough was 1.05 (0.88, 1.24) and AUC 0-21days was 0.87 (0.83, 0.92); the steady state C trough was 1.15 (1.05, 1.26) and AUC was 1.01 (0.94, 1.08) . Steady-state was achieved 6 to 9 weeks. The systemic accumulation ratio following administration of the approved recommended dosage of TECENTRIQ HYBREZA was 2.2. Absorption The mean absolute bioavailability (CV%) of atezolizumab was 72% (83%) and the median time (range) to reach maximum atezolizumab concentration (T max ) was 4.5 (2.2, 9) days. Distribution The volume of distribution of atezolizumab at steady state was 6.9 L. Elimination The atezolizumab clearance (CV%) was 0.2 L/day (29%) and the terminal half-life was 27 days. Atezolizumab clearance decreased over time, with a mean maximal reduction (CV%) from baseline value of 17% (41%); this decrease in clearance is not considered clinically significant. Specific Populations No clinically significant differences in the pharmacokinetics of atezolizumab were observed based on age, body weight, sex, albumin levels, tumor burden, region, race, mild or moderate renal impairment (estimated glomerular filtration rate 30 to 89 mL/minute/1.73 m 2 ), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3× ULN and any AST), level of PD-L1 expression, and performance status. Pediatric patients Atezolizumab exposure following subcutaneous administration of atezolizumab 1875 mg and 30,000 units hyaluronidase every 3 weeks in pediatric patients aged 12 years and older who weigh 40 kg or greater is predicted to be within range of those observed in adult patients at the same dosage. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of TECENTRIQ HYBREZA or of other atezolizumab products or hyaluronidase products. During the first year of treatment in the Study IMscin001 [see Clinical Studies (14.1) ], the incidence of ADA was 20% (43/221) and the incidence of neutralizing antibodies (NAb) in ADA-positive patients was 54% (21/39) for TECENTRIQ HYBREZA. The corresponding incidence of ADA was 14% (15/108) and NAb was 60% (9/15) for intravenous atezolizumab. In Study IMscin001, atezolizumab clearance increased by 29% in patients who received TECENTRIQ HYBREZA and who tested positive for ADA, compared to patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. Because of limited immunogenicity data the effect of ADA on the effectiveness of TECENTRIQ HYBREZA is unknown. There was no identified clinically significant effect of anti-atezolizumab antibodies on the safety of TECENTRIQ HYBREZA during the first 6 months of treatment. In Study IMscin001, the incidence of anti-rHuPH20 antibodies was 5.4% (12/224) and the incidence of NAb was 0% (0/12). Because of the low occurrence of anti-rHuPH20 antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics and/or safety of hyaluronidase in TECENTRIQ HYBREZA is unknown. Immunogenicity with Other Clinical Trials with Intravenous Atezolizumab: During the first year of treatment with intravenous atezolizumab across clinical studies of patients with NSCLC, SCLC, HCC melanoma and MIBC 13% to 36% of patients developed ADA to atezolizumab. Across clinical studies, the NAb incidence in ADA-positive patients was 24% to 83%. In OAK and IMbrave150, exploratory analyses showed that the subset of patients who were ADA-positive appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for ADA [see Clinical Studies (14.1 , 14.3) ] . In study IMpower150 and IMforte, the impact of ADA on efficacy did not appear to be clinically significant [see Clinical Studies (14.1) ] . In the remaining studies, there is insufficient information to characterize the effect of ADA on efficacy. Median atezolizumab clearance in patients who tested positive for ADA was 20% (range of 10% to 49%) higher as compared to atezolizumab clearance in patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions. The effect of NAb on atezolizumab exposure and safety did not appear to be clinically significant. The effect of NAb on key efficacy endpoints is uncertain due to small sample sizes." ], "mechanism_of_action": [ "12.1 Mechanism of Action PD-L1 may be expressed on tumor cells and/or tumor infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth. In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in TECENTRIQ HYBREZA acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours." ], "pharmacodynamics": [ "12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of atezolizumab and hyaluronidase have not been fully characterized." ], "pharmacokinetics": [ "12.3 Pharmacokinetics When comparing atezolizumab exposure following subcutaneous TECENTRIQ HYBREZA to that of intravenous atezolizumab in Study IMscin001 [see Clinical Studies (14.1) ], the geometric mean ratio (GMR) (90% CI) for Cycle 1 C trough was 1.05 (0.88, 1.24) and AUC 0-21days was 0.87 (0.83, 0.92); the steady state C trough was 1.15 (1.05, 1.26) and AUC was 1.01 (0.94, 1.08) . Steady-state was achieved 6 to 9 weeks. The systemic accumulation ratio following administration of the approved recommended dosage of TECENTRIQ HYBREZA was 2.2. Absorption The mean absolute bioavailability (CV%) of atezolizumab was 72% (83%) and the median time (range) to reach maximum atezolizumab concentration (T max ) was 4.5 (2.2, 9) days. Distribution The volume of distribution of atezolizumab at steady state was 6.9 L. Elimination The atezolizumab clearance (CV%) was 0.2 L/day (29%) and the terminal half-life was 27 days. Atezolizumab clearance decreased over time, with a mean maximal reduction (CV%) from baseline value of 17% (41%); this decrease in clearance is not considered clinically significant. Specific Populations No clinically significant differences in the pharmacokinetics of atezolizumab were observed based on age, body weight, sex, albumin levels, tumor burden, region, race, mild or moderate renal impairment (estimated glomerular filtration rate 30 to 89 mL/minute/1.73 m 2 ), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3× ULN and any AST), level of PD-L1 expression, and performance status. Pediatric patients Atezolizumab exposure following subcutaneous administration of atezolizumab 1875 mg and 30,000 units hyaluronidase every 3 weeks in pediatric patients aged 12 years and older who weigh 40 kg or greater is predicted to be within range of those observed in adult patients at the same dosage." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of atezolizumab for carcinogenicity or genotoxicity. Animal fertility studies have not been conducted with atezolizumab; however, an assessment of the male and female reproductive organs was included in a 26-week, repeat-dose toxicity study in cynomolgus monkeys. Weekly administration of atezolizumab to female monkeys at the highest dose tested caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately 6 times the AUC in patients receiving the recommended intravenous atezolizumab dose and was reversible. There was no effect on the male monkey reproductive organs. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when up to 220,000 units/kg of subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks, which is > 223 times higher than the human recommended dose for hyaluronidase, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters (e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data). 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of atezolizumab for carcinogenicity or genotoxicity. Animal fertility studies have not been conducted with atezolizumab; however, an assessment of the male and female reproductive organs was included in a 26-week, repeat-dose toxicity study in cynomolgus monkeys. Weekly administration of atezolizumab to female monkeys at the highest dose tested caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately 6 times the AUC in patients receiving the recommended intravenous atezolizumab dose and was reversible. There was no effect on the male monkey reproductive organs. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when up to 220,000 units/kg of subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks, which is > 223 times higher than the human recommended dose for hyaluronidase, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters (e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer NSCLC - TECENTRIQ HYBREZA IMscin001 (NCT03735121) was an open-label, multi-center, international, randomized study conducted in adult patients with locally advanced or metastatic NSCLC who were not exposed to cancer immunotherapy and who have disease progression following platinum-based chemotherapy. Patients were excluded if they had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; received a live, attenuated vaccine within 4 weeks prior to randomization; or received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive drugs within 2 weeks prior to randomization. A total of 371 patients were randomized 2:1 to receive either TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously in the thigh every 3 weeks (n = 247) or intravenous atezolizumab 1,200 mg every 3 weeks (n = 124) until disease progression or unacceptable toxicity. The primary outcome measure was atezolizumab exposure (C trough and AUC 0-21days ) of subcutaneous TECENTRIQ HYBREZA as compared to intravenous atezolizumab [see Clinical Pharmacology (12.3) ] . Additional descriptive efficacy outcome measures were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). The median age was 64 years (range: 27 to 85); 69% were male; 67% were White, 22% were Asian, and 0.8% were Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers. Sixty-five percent of patients had non-squamous histology, 5% had known EGFR mutations, 1.6% had known ALK rearrangements, 36% had known PD-L1 positive tumors, 16% had asymptomatic CNS metastases at baseline. Eighty percent of patients had received only one prior therapeutic regimen for NSCLC. At the primary analysis, the confirmed ORR was 9% (95% CI: 5, 13) in the subcutaneous TECENTRIQ HYBREZA arm and 8% (95% CI: 4, 14) in the intravenous atezolizumab arm. After further follow up, no notable differences in PFS and OS were observed between patients who received subcutaneous TECENTRIQ HYBREZA and patients who received intravenous atezolizumab. NSCLC Trials - Intravenous Atezolizumab The effectiveness of TECENTRIQ HYBREZA has been established for: adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells (IMpower010 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study). Use of TECENTRIQ HYBREZA for these NSCLC indications is supported by evidence from the adequate and well-controlled studies conducted with intravenous atezolizumab in these NSCLC populations and pharmacokinetics data that demonstrated comparable exposures to atezolizumab between TECENTRIQ HYBREZA and intravenous atezolizumab in the IMscin001 trial [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. Below is a description of the efficacy results of these adequate and well-controlled studies of intravenous atezolizumab in these NSCLC populations. Adjuvant Treatment of Early-stage NSCLC IMpower010 The efficacy of intravenous atezolizumab was evaluated in IMpower010 (NCT02486718), a multi-center, randomized, open-label trial for the adjuvant treatment of patients with NSCLC who had complete tumor resection and were eligible to receive cisplatin-based adjuvant chemotherapy. Eligible patients were required to have Stage IB (tumors ≥ 4 cm) – Stage IIIA NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system, 7th edition. Patients were excluded if they had a history of autoimmune disease; a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. A total of 1005 patients who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized (1:1) to receive intravenous atezolizumab 1200 mg intravenous infusion every 3 weeks for 16 cycles, unless disease recurrence or unacceptable toxicity occurred, or best supportive care (BSC). Randomization was stratified by sex, stage of disease, histology, and PD-L1 expression. Tumor assessments were conducted at baseline of the randomization phase and every 4 months for the first year following Cycle 1, Day 1 and then every 6 months until year five, then annually thereafter. The median age was 62 years (range: 26 to 84), and 67% of patients were male. The majority of patients were White (73%) and Asian (24%). Most patients were current or previous smokers (78%) and baseline Eastern Cooperative Oncology Group (ECOG) performance status in patients was 0 (55%) or 1 (44%). Overall, 12% of patients had Stage IB, 47% had Stage II and 41% had Stage IIIA disease. PD-L1 expression, defined as the percentage of tumor cells expressing PD-L1 as measured by the VENTANA PD-L1 (SP263) assay, was ≥ 1% in 53% of patients, < 1% in 44% and unknown in 2.6%. The primary efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator. The primary efficacy analysis population (n = 476) was patients with Stage II – IIIA NSCLC with PD-L1 expression on ≥ 1% of tumor cells (PD-L1 ≥ 1% TC). DFS was defined as the time from the date of randomization to the date of occurrence of any of the following: first documented recurrence of disease, new primary NSCLC, or death due to any cause, whichever occurred first. A key secondary efficacy outcome measure was overall survival (OS) in the intent-to-treat population. At the time of the interim DFS analysis, the study demonstrated a statistically significant improvement in DFS in the PD-L1 ≥ 1% TC, Stage II – IIIA patient population. Efficacy results are presented in Table 27 and Figure 1 . Table 27: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC Arm A: Intravenous Atezolizumab N = 248 Arm B: Best Supportive Care N = 228 CI = Confidence interval, NE = Not estimable, NR = Not reached Disease-Free Survival Number of events (%) 88 (35) 105 (46) Median, months NR 35.3 (95% CI) (36.1, NE) (29.0, NE) Hazard ratio Stratified by stage, sex, and histology (95% CI) 0.66 (0.50, 0.88) p-value 0.004 In a pre-specified secondary subgroup analysis of patients with PD-L1 TC ≥ 50% Stage II – IIIA NSCLC (n = 229), the median DFS was not reached (95% CI: 42.3 months, NE) for patients in the intravenous atezolizumab arm and was 35.7 months (95% CI: 29.7, NE) for patients in the best supportive care arm, with a HR of 0.43 (95% CI: 0.27, 0.68). In an exploratory subgroup analysis of patients with PD-L1 TC 1-49% Stage II – IIIA NSCLC (n = 247), the median DFS was 32.8 months (95% CI:29.4, NE) for patients in the intravenous atezolizumab arm and 31.4 months (95% CI: 24.0, NE) for patients in the best supportive care arm, with a HR of 0.87 (95% CI: 0.60, 1.26). Figure 1: Kaplan-Meier Plot of Disease-Free Survival in IMpower010 in Patients with Stage II – IIIA NSCLC with PD-L1 expression ≥ 1% TC At the time of the DFS interim analysis, 19% of patients in the PD-L1 ≥1% TC Stage II – IIIA patient population had died. An exploratory analysis of OS in this population resulted in a stratified HR of 0.77 (95% CI: 0.51, 1.17). Metastatic Chemotherapy-Naïve NSCLC IMpower110 The efficacy of intravenous atezolizumab was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC ≥ 1%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area [IC ≥ 1%]), who had received no prior chemotherapy for metastatic disease. PD-L1 tumor status was determined based on immunohistochemistry (IHC) testing using the VENTANA PD-L1 (SP142) Assay. The evaluation of efficacy is based on the subgroup of patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK genomic tumor aberrations. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. Randomization was stratified by sex, ECOG performance status, histology (non-squamous vs. squamous) and PD-L1 expression (TC ≥ 1% and any IC vs. TC < 1% and IC ≥ 1%). Patients were randomized (1:1) to receive one of the following treatment arms: Arm A: Intravenous atezolizumab 1200 mg every 3 weeks until disease progression or unacceptable toxicity Arm B: Platinum-based chemotherapy Arm B platinum-based chemotherapy regimens for non-squamous NSCLC consisted of cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) OR carboplatin (AUC 6 mg/mL/min) and pemetrexed (500 mg/m²) on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by pemetrexed (500 mg/m²) until disease progression or unacceptable toxicity. Arm B platinum-based chemotherapy regimens for squamous NSCLC consisted of cisplatin (75 mg/m²) on Day 1 with gemcitabine (1250 mg/m2) on Days 1 and 8 of each 21-day cycle OR carboplatin (AUC 5 mg/mL/min) on Day 1 with gemcitabine (1000 mg/m 2 ) on Days 1 and 8 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care until disease progression or unacceptable toxicity. Administration of intravenous atezolizumab was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. The major efficacy outcome measure was overall survival (OS) sequentially tested in the following subgroups of patients, excluding those with EGFR or ALK genomic tumor aberrations: TC ≥ 50% or IC ≥ 10%; TC ≥ 5% or IC ≥ 5%; and TC ≥ 1% or IC ≥ 1%. Among the 205 chemotherapy-naïve patients with stage IV NSCLC with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%) excluding those with EGFR or ALK genomic tumor aberrations, the median age was 65.0 years (range: 33 to 87), and 70% of patients were male. The majority of patients were White (82%) and Asian (17%). Baseline ECOG performance status was 0 (36%) or 1 (64%); 88% were current or previous smokers; and 76% of patients had non-squamous disease while 24% of patients had squamous disease. The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%) at the time of the OS interim analysis. There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC ≥ 5% or IC ≥ 5%; and TC ≥ 1% or IC ≥ 1%) at the interim or final analyses. Efficacy results for patients with NSCLC with high PD-L1 expression are presented in Table 28 and Figure 2 . Table 28: Efficacy Results from IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and without EGFR or ALK Genomic Tumor Aberrations Arm A: Intravenous Atezolizumab Arm B: Platinum-Based Chemotherapy N = 107 N = 98 CI = confidence interval; NE = not estimable Overall Survival Based on OS interim analysis. The median survival follow-up time in patients was 15.7 months Deaths (%) 44 (41%) 57 (58%) Median, months 20.2 13.1 (95% CI) (16.5, NE) (7.4, 16.5) Hazard ratio Stratified by sex and ECOG performance status (95% CI) 0.59 (0.40, 0.89) p-value Based on the stratified log-rank test compared to Arm A 0.0106 Compared to the allocated alpha of 0.0413 (two-sided) for this interim analysis Figure 2: Kaplan-Meier Plot of Overall Survival in IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and without EGFR or ALK Genomic Tumor Aberrations Investigator-assessed PFS showed an HR of 0.63 (95% CI: 0.45, 0.88), with median PFS of 8.1 months (95% CI: 6.8, 11.0) in the intravenous atezolizumab arm and 5 months (95% CI: 4.2, 5.7) in the platinum-based chemotherapy arm. The investigator-assessed confirmed ORR was 38% (95% CI: 29%, 48%) in the intravenous atezolizumab arm and 29% (95% CI: 20%, 39%) in the platinum-based chemotherapy arm. First-Line Metastatic Non-squamous NSCLC IMpower150 The efficacy of intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized (1:1:1), open-label trial in patients with metastatic non-squamous NSCLC. Patients with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease but could have received prior EGFR or ALK kinase inhibitor if appropriate, regardless of PD-L1 or T-effector gene (tGE) status and ECOG performance status 0 or 1 were eligible. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, or clear tumor infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions as seen on imaging. Randomization was stratified by sex, presence of liver metastases, and PD-L1 expression status on tumor cells (TC) and tumor-infiltrating immune cells (IC) as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following three treatment arms: Arm A: intravenous atezolizumab 1200 mg, paclitaxel 175 mg/m² or 200 mg/m² and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Arm B: intravenous atezolizumab 1200 mg, bevacizumab 15 mg/kg, paclitaxel 175 mg/m² or 200 mg/m², and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Arm C: bevacizumab 15 mg/kg, paclitaxel 175 mg/m² or 200 mg/m², and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Patients who had not experienced disease progression following the completion or cessation of platinum-based chemotherapy, received: Arm A: intravenous atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Arm B: intravenous atezolizumab 1200 mg and bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Arm C: bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumor specimens were evaluated prior to randomization for PD-L1 tumor expression using the VENTANA PD-L1 (SP142) assay at a central laboratory. Tumor tissue was collected at baseline for expression of tGE signature and evaluation was performed using a clinical trial assay in a central laboratory prior to the analysis of efficacy outcome measures. Major efficacy outcome measures for comparison of Arms B and C were progression free survival (PFS) by RECIST v1.1 in the tGE-WT (patients with high expression of T-effector gene signature [tGE], excluding those with EGFR- and ALK-positive NSCLC [WT]) and in the ITT-WT subpopulations and overall survival (OS) in the ITT-WT subpopulation. Additional efficacy outcome measures for comparison of Arms B and C or Arms A and C were PFS and OS in the ITT population, OS in the tGE-WT subpopulation, and ORR/DoR in the tGE-WT and ITT-WT subpopulations. A total of 1202 patients were enrolled across the three arms of whom 1045 were in the ITT-WT subpopulation and 447 were in the tGE-WT subpopulation. The demographic information is limited to the 800 patients enrolled in Arms B and C where efficacy has been demonstrated. The median age was 63 years (range: 31 to 90), and 60% of patients were male. The majority of patients were White (82%), 13% of patients were Asian, 10% were Hispanic, and 2% of patients were Black. Clinical sites in Asia (enrolling 13% of the study population) received paclitaxel at a dose of 175 mg/m2 while the remaining 87% received paclitaxel at a dose of 200 mg/m2. Approximately 14% of patients had liver metastases at baseline, and most patients were current or previous smokers (80%). Baseline ECOG performance status was 0 (43%) or 1 (57%). PD-L1 was TC3 and any IC in 12%, TC0/1/2 and IC2/3 in 13%, and TC0/1/2 and IC0/1 in 75%. The demographics for the 696 patients in the ITT-WT subpopulation were similar to the ITT population except for the absence of patients with EGFR- or ALK-positive NSCLC. The trial demonstrated a statistically significant improvement in PFS between Arms B and C in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate a significant difference for either subpopulation between Arms A and C based on the final PFS analyses. In the interim analysis of OS, a statistically significant improvement was observed for Arm B compared to Arm C, but not for Arm A compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 29 and Figure 3 . Table 29: Efficacy Results in ITT-WT Population in IMpower150 Arm C: Bevacizumab, Paclitaxel and Carboplatin Arm B: Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin Arm A: Intravenous Atezolizumab with Paclitaxel, and Carboplatin N = 337 N = 359 N = 349 CI = confidence interval Overall Survival Based on OS interim analysis Deaths (%) 197 (59%) 179 (50%) 179 (51%) Median, months 14.7 19.2 19.4 (95% CI) (13.3, 16.9) (17.0, 23.8) (15.7, 21.3) Hazard ratio Stratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI) --- 0.78 (0.64, 0.96) 0.84 (0.72, 1.08) p-value Based on the stratified log-rank test compared to Arm C --- 0.016 Compared to the allocated α=0.0174 (two sided) for this interim analysis 0.204 Compared to the allocated α=0.0128 (two sided) for this interim analysis Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of events (%) 247 (73%) 247 (69%) 245 (70%) Median, months 7.0 8.5 6.7 (95% CI) (6.3, 7.9) (7.3, 9.7) (5.6, 6.9) Hazard ratio (95% CI) --- 0.71 (0.59, 0.85) 0.94 (0.79, 1.13) p-value --- 0.0002 Compared to the allocated α=0.006 (two sided) for the final PFS analysis 0.5219 Objective Response Rate Number of responders (%) 142 (42%) 196 (55%) 150 (43%) (95% CI) (37, 48) (49, 60) (38, 48) Complete Response 3 (1%) 14 (4%) 9 (3%) Partial Response 139 (41%) 182 (51%) 141 (40%) Duration of Response n = 142 n = 196 n = 150 Median, months 6.5 10.8 9.5 (95% CI) (5.6, 7.6) (8.4, 13.9) (7.0, 13.0) Figure 3: Kaplan-Meier Curves for Overall Survival in ITT-WT Population in IMpower150 Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (70%) [see, Clinical Pharmacology (12.6) ] . In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly, ADA negative patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were compared with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, tobacco history, metastatic site, TC level, and IC level. The hazard ratio comparing the ADA-positive subgroup with its matched control was 0.69 (95% CI: 0.44, 1.07). The hazard ratio comparing the ADA-negative subgroup with its matched control was 0.64 (95% CI: 0.46, 0.90). IMpower130 The efficacy of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in patients with stage IV non-squamous NSCLC. Patients with Stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease, but could have received prior EGFR or ALK kinase inhibitor, if appropriate, were eligible. The trial excluded patients with history of autoimmune disease, administration of live attenuated vaccine within 28 days prior to randomization, administration of immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, and active or untreated CNS metastases. Randomization was stratified by sex, presence of liver metastases, and PD-L1 tumor expression according to the VENTANA PD-L1 (SP142) assay as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following treatment regimens: Intravenous atezolizumab 1200 mg on Day 1, paclitaxel protein-bound 100 mg/m² on Days 1, 8, and 15, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by intravenous atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or Paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care or pemetrexed. Tumor assessments were conducted every 6 weeks for the first 48 weeks, then every 9 weeks thereafter. Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of patients evaluated for and documented to have no EGFR or ALK genomic tumor aberrations (ITT-WT). A total of 724 patients were enrolled; of these, 681 (94%) were in the ITT-WT population. The median age was 64 years (range: 18 to 86) and 59% were male. The majority of patients were White (90%), 2% of patients were Asian, 5% were Hispanic, and 4% were Black. Baseline ECOG performance status was 0 (41%) or 1 (58%). Most patients were current or previous smokers (90%). PD-L1 tumor expression was TC0/1/2 and IC0/1 in 73%; TC3 and any IC in 14%; and TC0/1/2 and IC2/3 in 13%. Efficacy results for the ITT-WT population are presented in Table 30 and Figure 4 . Table 30: Efficacy Results from IMpower130 Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin Paclitaxel Protein-Bound and Carboplatin CI = confidence interval Overall Survival Based on OS interim analysis n = 453 n = 228 Deaths (%) 228 (50%) 131 (57%) Median, months 18.6 13.9 (95% CI) (15.7, 21.1) (12.0, 18.7) Hazard ratio Stratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI) 0.80 (0.64, 0.99) p-value Based on the stratified log-rank test 0.0384 Compared to the allocated α=0.0428 (two sided) for this interim analysis Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) n = 453 n = 228 Number of events (%) 330 (73%) 177 (78%) Median, months 7.2 6.5 (95% CI) (6.7, 8.3) (5.6, 7.4) Hazard ratio (95% CI) 0.75 (0.63, 0.91) p-value 0.0024 Compared to the allocated α=0.006 (two sided) for the final PFS analysis Overall Response Rate , Confirmed response n = 453 n = 228 Number of responders (%) 207 (46%) 74 (32%) (95% CI) (41, 50) (26, 39) Complete Response 22 (5%) 2 (1%) Partial Response 185 (41%) 72 (32%) Duration of Response , n = 207 n = 74 Median, months 10.8 7.8 (95% CI) (9.0, 14.4) (6.8, 10.9) Figure 4: Kaplan-Meier Curves for Overall Survival in IMpower130 Previously Treated Metastatic NSCLC OAK The efficacy of intravenous atezolizumab was evaluated in a multicenter, international, randomized (1:1), open-label study (OAK; NCT02008227) conducted in patients with locally advanced or metastatic NSCLC whose disease progressed during or following a platinum-containing regimen. Patients with a history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 2 weeks prior to enrollment were ineligible. Randomization was stratified by PD-L1 expression tumor-infiltrating immune cells (IC), the number of prior chemotherapy regimens (1 vs. 2), and histology (squamous vs. non-squamous). Patients were randomized to receive intravenous atezolizumab 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel 75 mg/m 2 intravenously every 3 weeks until unacceptable toxicity or disease progression. Tumor assessments were conducted every 6 weeks for the first 36 weeks and every 9 weeks thereafter. Major efficacy outcome measure was overall survival (OS) in the first 850 randomized patients and OS in the subgroup of patients with PD-L1-expressing tumors (defined as ≥ 1% PD-L1 expression on tumor cells [TC] or immune cells [IC]). Additional efficacy outcome measures were OS in all randomized patients (n = 1225), OS in subgroups based on PD-L1 expression, overall response rate (ORR), and progression free survival as assessed by the investigator per RECIST v.1.1. Among the first 850 randomized patients, the median age was 64 years (33 to 85 years) and 47% were ≥ 65 years old; 61% were male; 70% were White and 21% were Asian; 15% were current smokers and 67% were former smokers; and 37% had baseline ECOG PS of 0 and 63% had a baseline ECOG PS of 1. Nearly all (94%) had metastatic disease, 74% had non-squamous histology, 75% had received only one prior platinum-based chemotherapy regimen, and 55% of patients had PD-L1-expressing tumors. Efficacy results are presented in Table 31 and Figure 5 Table 31: Efficacy Results in OAK Intravenous Atezolizumab Docetaxel CI = confidence interval; NE = not estimable Overall Survival in first 850 patients Number of patients N = 425 N = 425 Deaths (%) 271 (64%) 298 (70%) Median, months 13.8 9.6 (95% CI) (11.8, 15.7) (8.6, 11.2) Hazard ratio Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI) 0.74 (0.63, 0.87) p-value Based on the stratified log-rank test 0.0004 Compared to the pre-specified allocated α of 0.03 for this analysis Progression-Free Survival Number of Patients N = 425 N = 425 Events (%) 380 (89%) 375 (88%) Progression (%) 332 (78%) 290 (68%) Deaths (%) 48 (11%) 85 (20%) Median, months 2.8 4.0 (95% CI) (2.6, 3.0) (3.3, 4.2) Hazard ratio (95% CI) 0.95 (0.82, 1.10) Overall Response Rate Per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of Patients N = 425 N = 425 ORR, n (%) 58 (14%) 57 (13%) (95% CI) (11%, 17%) (10%, 17%) Complete Response 6 (1%) 1 (0.2%) Partial Response 52 (12%) 56 (13%) Duration of Response N = 58 N = 57 Median, months 16.3 6.2 (95% CI) (10.0, NE) (4.9, 7.6) Overall Survival in all 1225 patients Number of patients N = 613 N = 612 Deaths (%) 384 (63%) 409 (67%) Median, months 13.3 9.8 (95% CI) (11.3, 14.9) (8.9, 11.3) Hazard ratio (95% CI) 0.79 (0.69, 0.91) p-value 0.0013 Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary Figure 5: Kaplan-Meier Curves of Overall Survival in the First 850 Patients Randomized in OAK Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define the PD-L1 expression subgroups for pre-specified analyses. Of the 850 patients, 16% were classified as having high PD-L1 expression, defined as having PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was 0.41 (95% CI: 0.27, 0.64) in the high PD-L1 expression subgroup and 0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression. Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (79%) [see Clinical Pharmacology (12.6) ]. ADA positive patients by week 4 appeared to have similar OS compared to docetaxel-treated patients. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the intravenous atezolizumab arm with a matched population in the docetaxel arm and ADA negative patients in the intravenous atezolizumab arm with a matched population in the docetaxel arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, histology (squamous vs. non-squamous), baseline albumin, baseline LDH, gender, tobacco history, metastases status (advanced or local), metastatic site, TC level, and IC level. The hazard ratio comparing the ADA positive subgroup with its matched control was 0.89 (95% CI: 0.61, 1.3). The hazard ratio comparing the ADA negative subgroup with its matched control was 0.68 (95% CI: 0.55, 0.83). Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 14.2 Small Cell Lung Cancer The efficacy of TECENTRIQ HYBREZA in combination with chemotherapy for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) has been established in adequate and well-controlled studies of intravenous atezolizumab. Below is a description of the efficacy results of these adequate and well-controlled studies of intravenous atezolizumab in combination with chemotherapy in ES-SCLC (IMpower133 and IMforte studies). Small Cell Lung Cancer (SCLC) IMpower133 The efficacy of intravenous atezolizumab with carboplatin and etoposide was investigated in IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC. IMpower133 enrolled patients with ES-SCLC who had received no prior chemotherapy for extensive stage disease and ECOG performance status 0 or 1. The trial excluded patients with active or untreated CNS metastases, history of autoimmune disease, administration of a live, attenuated vaccine within 4 weeks prior to randomization, or administration of systemic immunosuppressive medications within 1 week prior to randomization. Randomization was stratified by sex, ECOG performance status, and presence of brain metastases. Patients were randomized to receive one of the following two treatment arms: intravenous atezolizumab 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m 2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles followed by intravenous atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or placebo and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m 2 intravenously on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles followed by placebo once every 3 weeks until disease progression or unacceptable toxicity. Administration of intravenous atezolizumab was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Patients treated beyond disease progression had tumor assessment conducted every 6 weeks until treatment discontinuation. Major efficacy outcome measures were OS and PFS as assessed by investigator per RECIST v1.1 in the intent-to-treat population. Additional efficacy outcome measures included ORR and DoR as assessed by investigator per RECIST v1.1. A total of 403 patients were randomized, including 201 to the intravenous atezolizumab arm and 202 to the chemotherapy alone arm. The median age was 64 years (range: 26 to 90) and 65% were male. The majority of patients were White (80%); 17% were Asian, 4% were Hispanic and 1% were Black. Baseline ECOG performance status was 0 (35%) or 1 (65%); 9% of patients had a history of brain metastases, and 97% were current or previous smokers. Efficacy results are presented in Table 32 and Figure 6 . Table 32: Efficacy Results from IMpower133 Intravenous Atezolizumab with Carboplatin and Etoposide Placebo with Carboplatin and Etoposide CI = confidence interval Overall Survival N = 201 N = 202 Deaths (%) 104 (52%) 134 (66%) Median, months 12.3 10.3 (95% CI) (10.8, 15.9) (9.3, 11.3) Hazard ratio Stratified by sex and ECOG performance status (95% CI) 0.70 (0.54, 0.91) p-value Based on the stratified log-rank test , Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary 0.0069 Progression-Free Survival As determined by investigator assessment , per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) N = 201 N = 202 Number of events (%) 171 (85%) 189 (94%) Median, months 5.2 4.3 (95% CI) (4.4, 5.6) (4.2, 4.5) Hazard ratio (95% CI) 0.77 (0.62, 0.96) p-value , Compared to the allocated α of 0.05 for this analysis 0.0170 Objective Response Rate , , Confirmed response N = 201 N = 202 Number of responders (%) 121 (60%) 130 (64%) (95% CI) (53, 67) (57, 71) Complete Response (%) 5 (2%) 2 (1%) Partial Response (%) 116 (58%) 128 (63%) Duration of Response , , N = 121 N = 130 Median, months 4.2 3.9 (95% CI) (4.1, 4.5) (3.1, 4.2) Figure 6: Kaplan-Meier Plot of Overall Survival in IMpower133 Figure 6 IMforte The efficacy of intravenous atezolizumab in combination with lurbinectedin as maintenance treatment was evaluated in IMforte (NCT05091567), a randomized, multicenter, open-label study in patients with ES-SCLC. Patients were eligible if their disease had not progressed after completion of four cycles of intravenous atezolizumab, carboplatin and etoposide (induction treatment) and they had an ECOG performance status of 0 or 1. The trial excluded patients with CNS metastases, history of autoimmune disease, or administration of systemic immunosuppressive medications within 1 week prior to enrollment. Unless contraindicated, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was mandated for patients assigned to the intravenous atezolizumab with lurbinectedin arm. The trial randomized 483 patients who had not experienced disease progression following the completion of four cycles of intravenous atezolizumab with carboplatin and etoposide to one of the following two treatment arms: Intravenous atezolizumab 1200 mg IV in combination with lurbinectedin 3.2 mg/m 2 IV once every 3 weeks until disease progression or unacceptable toxicity, or Intravenous atezolizumab 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity Randomization was stratified by ECOG performance status prior to randomization (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN) prior to randomization, presence of liver metastases prior to initial study enrollment (yes vs. no), and prior receipt of prophylactic cranial irradiation (yes vs. no). The major efficacy outcome measures were OS and PFS by Independent Review Facility per RECIST v1.1. A total of 483 patients were randomized, including 242 to the intravenous atezolizumab with lurbinectedin arm and 241 to the intravenous atezolizumab arm. The median age was 66 years (range 35 to 85 years); 63% male; 82% White; 13% Asian; 0.8% were Black or African American; 7% were of Hispanic or Latino ethnicity and 98% were current or previous smokers. Baseline ECOG performance status was 0 (43%) or 1 (57%). Efficacy results are presented in Table 33 and Figures 7 and 8 . Table 33: Efficacy Results from IMforte Intravenous Atezolizumab with Lurbinectedin N=242 Intravenous Atezolizumab N=241 CI=confidence interval Overall Survival Measured from the time of randomization Deaths (%) 113 (47%) 136 (56%) Median, months 13.2 10.6 (95% CI) (11.9, 16.4) (9.5, 12.2) Hazard ratio Stratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranial irradiation (95% CI) 0.73 (0.57, 0.95) p-value Based on the stratified log-rank test , Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis. 0.0174 Progression-Free Survival , As determined by an IRF , per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of events (%) 174 (72%) 202 (84%) Median, months 5.4 2.1 (95% CI) (4.2, 5.8) (1.6, 2.7) Hazard ratio (95% CI) 0.54 (0.43, 0.67) p-value , Compared to the allocated alpha of 0.001 (two- sided) for this final PFS analysis. <0.0001 Figure 7: Kaplan-Meier Plot of IRF-assessed Progression-Free Survival in IMforte Figure 8: Kaplan-Meier Plot of Overall Survival in IMforte Figure 7 Figure 8 14.3 Hepatocellular Carcinoma The efficacy of TECENTRIQ HYBREZA in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for HCC. Below is a description of the efficacy results of intravenous atezolizumab in combination with bevacizumab in this adequate and well-controlled HCC trial. Hepatocellular Carcinoma IMbrave150 The efficacy of intravenous atezolizumab in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (< 400 vs. ≥ 400 ng/mL), and by ECOG performance status (0 vs. 1). A total of 501 patients were randomized (2:1) to receive either intravenous atezolizumab as an intravenous infusion of 1200 mg, followed by 15 mg/kg bevacizumab, on the same day every 3 weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either intravenous atezolizumab or bevacizumab (e.g., due to adverse events) and continue on monotherapy until disease progression or unacceptable toxicity associated with the monotherapy. The study enrolled patients who were ECOG performance score 0 or 1 and who had not received prior systemic treatment. Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh B or C cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter. The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88) and 83% of patients were male. The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥ 400 ng/mL. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22%, and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B, and 3% had stage A. The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) per RECIST v1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST. Efficacy results are presented in Table 34 and Figure 9 . Table 34: Efficacy Results from IMbrave150 Intravenous Atezolizumab in combination with Bevacizumab (N= 336) Sorafenib (N=165) + Denotes a censored value CI = confidence interval; HCC mRECIST = Modified RECIST Assessment for Hepatocellular Carcinoma; NE = not estimable; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors v1.1 Overall Survival Number of deaths (%) 96 (29) 65 (39) Median OS in months NE 13.2 (95% CI) (NE, NE) (10.4, NE) Hazard ratio Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (< 400 vs. ≥ 400 ng/mL) (95% CI) 0.58 (0.42, 0.79) p-value Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method 0.0006 Progression-Free Survival Per independent radiology review Number of events (%) 197 (59) 109 (66) Median PFS in months (95% CI) 6.8 (5.8, 8.3) 4.3 (4.0, 5.6) Hazard ratio (95% CI) 0.59 (0.47, 0.76) p-value < 0.0001 Overall Response Rate , Confirmed responses (ORR), RECIST 1.1 Number of responders (%) 93 (28) 19 (12) (95% CI) (23, 33) (7,17) p-value Based on two-sided Cochran-Mantel-Haesnszel test < 0.0001 Complete responses, n (%) 22 (7) 0 Partial responses, n (%) 71 (21) 19 (12) Duration of Response , (DOR) RECIST 1.1 (n=93) (n=19) Median DOR in months NE 6.3 (95% CI) (NE, NE) (4.7, NE) Range (months) (1.3+, 13.4+) (1.4+, 9.1+) Overall Response Rate , (ORR), HCC mRECIST Number of responders (%) 112 (33) 21 (13) (95% CI) (28, 39) (8, 19) p-value < 0.0001 Complete responses, n (%) 37 (11) 3 (1.8) Partial responses, n (%) 75 (22) 18 (11) Duration of Response , (DOR) HCC mRECIST (n=112) (n=21) Median DOR in months NE 6.3 (95% CI) (NE, NE) (4.9, NE) Range (months) (1.3+, 13.4+) (1.4+, 9.1+) Figure 9: Kaplan-Meier Plot of Overall Survival in IMbrave150 Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6 [see Clinical Pharmacology (12.6) ] . ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients. In an exploratory analysis, inverse probability weighting was conducted to compare ADA-positive patients and ADA-negative patients in the intravenous atezolizumab and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (< 400 ng/mL vs ≥ 400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs. HCV vs. non-viral) and Child-Pugh Score (A5 vs. A6). The OS hazard ratio comparing the ADA-positive subgroup of the intravenous atezolizumab and bevacizumab arm to sorafenib was 0.93 (95% CI: 0.57, 1.53). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.39 (95% CI: 0.26, 0.60). Figure 9 14.4 Melanoma The efficacy of TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for BRAF V600 mutation-positive unresectable or metastatic melanoma. Below is a description of the efficacy results of intravenous atezolizumab in combination with cobimetinib and vemurafenib in this adequate and well-controlled melanoma trial. Metastatic Melanoma IMspire150 The efficacy of intravenous atezolizumab in combination with cobimetinib and vemurafenib was evaluated in a double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150; NCT02908672) conducted in 514 patients. Randomization was stratified by geographic location (North America vs. Europe vs. Australia, New Zealand, and others) and baseline lactate dehydrogenase (LDH) [less than or equal to upper limit of normal (ULN) vs. greater than ULN]. Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by a locally available test and centrally confirmed with the FoundationOne™ assay. Patients were excluded if they had history of autoimmune disease; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; and active or untreated CNS metastases. Intravenous atezolizumab was initiated after patients received a 28-day treatment cycle of cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 960 mg orally twice daily Days 1-21 and 720 mg orally twice daily Days 22-28. Patients received intravenous atezolizumab 840 mg intravenous infusion over 60 minutes every 2 weeks in combination with cobimetinib 60 mg orally once daily and vemurafenib 720 mg orally twice daily, or placebo in combination with cobimetinib 60 mg orally once daily and vemurafenib 960 mg orally twice daily. Treatment continued until disease progression or unacceptable toxicity. There was no crossover at the time of disease progression. Tumor assessments were performed every 8 weeks (± 1 week) for the first 24 months and every 12 weeks (± 1 week) thereafter. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes included PFS assessed by an independent central review, investigator-assessed ORR, OS, and DOR. The median age of the study population was 54 years (range: 22–88), 58% of patients were male, 95% were White, a baseline ECOG performance status of 0 (77%) or 1 (23%), 33% had elevated LDH, 94% had metastatic disease, 60% were Stage IV (M1C), 56% had less than three metastatic sites at baseline, 3% had prior treatment for brain metastases, 30% had liver metastases at baseline, and 14% had received prior adjuvant systemic therapy. Based on central testing, 74% were identified as having a V600E mutation, 11% as having V600K mutation, and 1% as having V600D or V600R mutations. Efficacy results are summarized in Table 35 and Figure 10 . Patients had a median survival follow up time of 18.9 months. Table 35: Efficacy Results from IMspire150 Intravenous Atezolizumab + Cobimetinib + Vemurafenib N = 256 Placebo + Cobimetinib + Vemurafenib N = 258 Progression-Free Survival As determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI = confidence interval Number of events (%) 148 (58) 179 (69) Median, months 15.1 10.6 (95% CI) (11.4, 18.4) (9.3, 12.7) Hazard ratio Stratified by baseline LDH (95% CI) 0.78 (0.63, 0.97) p-value Based on the stratified log-rank test 0.0249 Overall Response Rate , Confirmed responses Number of responders (%) 170 (66) 168 (65) (95% CI) (60, 72) (59, 71) Complete responses, n (%) 41 (16) 46 (18) Partial response, n (%) 129 (50) 122 (47) Duration of Response , n = 170 n = 168 Median, months 20.4 12.5 (95% CI) (15.1, NE) (10.7, 16.6) Figure 10: Kaplan-Meier Plot for Progression-Free Survival in IMspire150 At a pre-specified analysis at the time of the primary analysis of PFS, the OS data were not mature. The median OS was 28.8 months with 93 (36%) deaths in the intravenous atezolizumab plus cobimetinib and vemurafenib arm, and 25.1 months with 112 (43%) deaths in the placebo plus cobimetinib and vemurafenib arm. The hazard ratio for OS was 0.85 (95% CI: 0.64, 1.11) and the p-value was 0.2310. Figure 10 14.5 Alveolar Soft Part Sarcoma The efficacy of TECENTRIQ HYBREZA as monotherapy for the treatment of adult patients and pediatric patients 12 years of age or older with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS. Below is a description of the efficacy results of intravenous atezolizumab in this adequate and well-controlled ASPS trial. The efficacy of intravenous atezolizumab was evaluated in study ML39345 (NCT03141684), an open-label, single-arm study, in 49 adult and pediatric patients aged 2 years and older with unresectable or metastatic ASPS. Eligible patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of ≤ 2. Patients were excluded if they had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. Adult patients received 1200 mg intravenously and pediatric patients received 15 mg/kg (up to a maximum of 1200 mg) intravenously once every 21 days until disease progression or unacceptable toxicity. The major efficacy outcomes were Overall Response Rate (ORR) and Duration of Response (DOR) by Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A total of 49 patients were enrolled. The median age of patients was 31 years (range: 12–70); 2% of adult patients (n = 47) were ≥ 65 years of age and the pediatric patients (n = 2) were ≥ 12 years of age; 51% of patients were female, 55% White, 29% Black or African American, 10% Asian; 53% had an ECOG performance status of 0 and 45% had an ECOG performance status of 1. All patients had prior surgery for ASPS and 55% received at least one prior line of treatment for ASPS; 55% received radiotherapy and 53% received chemotherapy. Of the patients who reported staging at initial diagnosis, all were Stage IV. Efficacy results of this study are summarized in Table 36 . Table 36: Efficacy Results from Study ML39345 Endpoint All Patients (N=49) CI: confidence interval; N: number of patients; +: Censored Overall Response Rate (95% CI) 95% CI based on Clopper-Pearson exact method. 24% (13, 39) Complete responses, n 0 Partial responses, n (%) 12 (24) Duration of Response Median, month NE (95% CI) (17.0, NE) Range 1+, 41+ Durability of response ≥ 6 months, n (%) 8 (67%) ≥ 12 months, n (%) 5 (42%) 14.6 Muscle Invasive Bladder Cancer The efficacy of TECENTRIQ HYBREZA as an adjuvant treatment for adult patients with MIBC after cystectomy who have ctDNA MRD has been established in an adequate and well-controlled study of intravenous atezolizumab for MIBC. Below is a description of the efficacy results of intravenous atezolizumab in this adequate and well-controlled MIBC trial. Muscle Invasive Bladder Cancer IMvigor011 The efficacy of intravenous atezolizumab was evaluated in IMvigor011 (NCT04660344), a multi-center, randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD). The trial enrolled patients with histologically confirmed MIBC who underwent radical cystectomy with lymph node dissection. Eligible patients had pathologic tumor staging of pT2-4a and/or positive lymph nodes following cystectomy, with no evidence of residual disease or metastasis on imaging, confirmed within 28 days before randomization. Patients were eligible regardless of whether they had received prior neoadjuvant chemotherapy (NAC) or not. Patients were excluded if they had received any anti-cancer therapy within 3 weeks prior to trial enrollment or had a history of autoimmune disease. Serial ctDNA MRD testing was performed every 6 weeks for 9 months starting at least 6 weeks after cystectomy with a final test at one year. Patients who did not develop ctDNA MRD within the testing period were monitored without study treatment, while those who had ctDNA MRD were screened for the treatment phase by confirming that they remained free of radiographic disease. The ctDNA MRD status was determined using either a Signatera™ clinical trial assay (whole exome-based tumor NGS sequencing and 16-plex NGS-based plasma sequencing) or a clinical trial assay performed locally in China. Randomization was stratified by nodal status (positive vs. negative), tumor stage (≤(y)pT2 vs. (y)pT3/pT4), PD-L1 immunohistochemistry (IHC) (IC <5% vs. IC ≥5%), and time from cystectomy to first ctDNA MRD positive sample (≤20 weeks vs. >20 weeks). A total of 250 patients were randomized 2:1 to receive either: Arm A: Intravenous atezolizumab 1680 mg intravenously every 4 weeks on Day 1 of each 28 -day cycle. Arm B: Placebo intravenously every 4 weeks on Day 1 of each 28-day cycle Treatment continued for up to 12 cycles or 1 year (whichever occurred first) unless there was disease recurrence, or unacceptable toxicity. Tumor assessments were conducted every 9 weeks for the first two years, then every 12 weeks for year 3, and every 24 weeks thereafter. Among the 250 patients, the median age was 69 years (range: 42 to 87); 83% were male. The majority of patients were White (62%), 32% Asian, 1.6% American Indian or Alaska Native, 0.8% Black or African American, and 4.4% unknown; 11% Hispanic or Latino ethnicity, 84% not Hispanic or Latino, and 4% not reported/unknown ethnicity. Baseline ECOG performance status was 0 in 66% of patients and 1 in 32%. A total of 48% of patients in the TECENTRIQ arm received prior platinum containing neoadjuvant chemotherapy. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). Overall Survival (OS) was an additional efficacy measure. The study demonstrated statistically significant improvements in DFS and OS for patients randomized to the intravenous atezolizumab arm compared with placebo. Efficacy results are presented in Table 37 and Figures 11 and 12 . Table 37: Efficacy Results from IMvigor011 Intravenous Atezolizumab N=167 Placebo N=83 CI=confidence interval; NE=not estimable Investigator - assessed DFS Number of events (%) 112 (67%) 66 (80%) Median Based on Kaplan-Meier estimates , months 9.9 4.8 (95% CI) (7.2, 12.7) (4.1, 8.3) Hazard ratio Based on stratified Cox proportional hazards model , Stratified by programmed death-ligand 1 (PD-L1) status, nodal status, tumor stage after cystectomy (95% CI) 0.64 (0.47, 0.87) p-value , Based on stratified log-rank test 0.0047 Overall survival Number of deaths (%) 60 (36%) 36 (43%) Median , months 32.8 21.1 (95% CI) (27.7, NE) (14.7, NE) Hazard ratio , (95% CI) 0.59 (0.39, 0.90) p-value , 0.0131 Figure 11: Kaplan-Meier Plot of Investigator-Assessed Disease-Free Survival in IMvigor011 Figure 12: Kaplan-Meier Plot of Overall Survival in IMvigor011 In a pre-specified exploratory analysis based on time from cystectomy to first ctDNA MRD positive sample, the unstratified hazard ratio (HR) for investigator-assessed DFS in the subgroup of patients who had ≤20 weeks to first ctDNA MRD positive sample (n=176), was 0.52 (95% CI: 0.37, 0.74), with median DFS of 8.3 months (95% CI: 6.2, 12.7) in the intravenous atezolizumab arm and 4.1 months (95% CI: 2.3, 6.2) in the placebo arm. The unstratified HR for OS was 0.63 (95% CI: 0.39, 1.00), with median OS of 32.8 months (95% CI: 24.4, not reached) in the intravenous atezolizumab arm and 18.2 months (95% CI: 13.1, not reached) in the placebo arm. In the subgroup of patients who had >20 weeks to first ctDNA MRD positive sample (n=74), the unstratified HR for investigator-assessed DFS was 1.04 (95% CI: 0.54, 1.97), with median DFS of 10.5 months (95% CI: 6.9, 20.9) in the intravenous atezolizumab arm and 10.5 months (95% CI: 6.5, 20.5) in the placebo arm. The unstratified HR for OS was 0.77 (95% CI: 0.30, 1.96); median OS was not reached in either arm (95% CI: 21.1 months, not reached in the intravenous atezolizumab arm and 18.4 months, not reached in the placebo arm). Figure 11 Figure 12 14.7 Patient Experience The IMscin002 study (NCT03735121) was a randomized, multi-center, open-label cross-over trial conducted in 179 patients with either PD-L1-positive early-stage NSCLC receiving adjuvant treatment or were chemotherapy-naïve with high PD-L1 stage IV NSCLC. Patients were randomized (1:1) to receive 3 cycles of TECENTRIQ HYBREZA followed by 3 cycles of intravenous atezolizumab (Arm A) or 3 cycles of intravenous atezolizumab followed by 3 cycles of TECENTRIQ HYBREZA (Arm B). Of the 126 eligible patients, 123 (98%) completed the patient preference questionnaire at the beginning of cycle 6 or after at least two consecutive cycles of each treatment method was administered in case of treatment discontinuation prior to cycle 6. Eighty-seven of 123 patients (71%) reported preferring subcutaneous administration of TECENTRIQ HYBREZA over intravenous atezolizumab and the most common reason was that administration required less time in the clinic; 26 out of 123 patients (21%) reported preferring intravenous atezolizumab over TECENTRIQ HYBREZA and the most common reason was that it felt more comfortable during administration; and 10 out of 123 patients (8%) had no preference for the route of administration. Patients in both arms could continue to receive treatment after the crossover period for up to 16 cycles (patients with early-stage NSCLC) or until disease progression or unacceptable toxicity (patients with stage IV NSCLC). Of the 107 patients who reached the treatment continuation period, 85 (79%) patients (42 from IV/SC and 43 from SC/IV) chose to continue treatment with the SC route of administration." ], "clinical_studies_table": [ "
Table 27: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC
Arm A: Intravenous Atezolizumab N = 248Arm B: Best Supportive Care N = 228
CI = Confidence interval, NE = Not estimable, NR = Not reached
Disease-Free Survival
Number of events (%)88 (35)105 (46)
Median, monthsNR35.3
(95% CI)(36.1, NE)(29.0, NE)
Hazard ratioStratified by stage, sex, and histology (95% CI)0.66 (0.50, 0.88)
p-value0.004
", "
Table 28: Efficacy Results from IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and without EGFR or ALK Genomic Tumor Aberrations
Arm A: Intravenous AtezolizumabArm B: Platinum-Based Chemotherapy
N = 107N = 98
CI = confidence interval; NE = not estimable
Overall SurvivalBased on OS interim analysis. The median survival follow-up time in patients was 15.7 months
Deaths (%)44 (41%)57 (58%)
Median, months20.213.1
(95% CI)(16.5, NE)(7.4, 16.5)
Hazard ratioStratified by sex and ECOG performance status (95% CI)0.59 (0.40, 0.89)
p-valueBased on the stratified log-rank test compared to Arm A0.0106Compared to the allocated alpha of 0.0413 (two-sided) for this interim analysis
", "
Table 29: Efficacy Results in ITT-WT Population in IMpower150
Arm C: Bevacizumab, Paclitaxel and CarboplatinArm B: Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and CarboplatinArm A: Intravenous Atezolizumab with Paclitaxel, and Carboplatin
N = 337N = 359N = 349
CI = confidence interval
Overall SurvivalBased on OS interim analysis
Deaths (%)197 (59%)179 (50%)179 (51%)
Median, months14.719.219.4
(95% CI)(13.3, 16.9)(17.0, 23.8)(15.7, 21.3)
Hazard ratioStratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI)---0.78 (0.64, 0.96)0.84 (0.72, 1.08)
p-valueBased on the stratified log-rank test compared to Arm C---0.016Compared to the allocated α=0.0174 (two sided) for this interim analysis0.204Compared to the allocated α=0.0128 (two sided) for this interim analysis
Progression-Free SurvivalAs determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of events (%)247 (73%)247 (69%)245 (70%)
Median, months7.08.56.7
(95% CI)(6.3, 7.9)(7.3, 9.7)(5.6, 6.9)
Hazard ratio (95% CI)---0.71 (0.59, 0.85)0.94 (0.79, 1.13)
p-value---0.0002Compared to the allocated α=0.006 (two sided) for the final PFS analysis0.5219
Objective Response Rate
Number of responders (%)142 (42%)196 (55%)150 (43%)
(95% CI)(37, 48)(49, 60)(38, 48)
Complete Response3 (1%)14 (4%)9 (3%)
Partial Response139 (41%)182 (51%)141 (40%)
Duration of Responsen = 142n = 196n = 150
Median, months6.510.89.5
(95% CI)(5.6, 7.6)(8.4, 13.9)(7.0, 13.0)
", "
Table 30: Efficacy Results from IMpower130
Intravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinPaclitaxel Protein-Bound and Carboplatin
CI = confidence interval
Overall SurvivalBased on OS interim analysisn = 453n = 228
Deaths (%)228 (50%)131 (57%)
Median, months18.613.9
(95% CI)(15.7, 21.1)(12.0, 18.7)
Hazard ratioStratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI)0.80 (0.64, 0.99)
p-valueBased on the stratified log-rank test0.0384Compared to the allocated α=0.0428 (two sided) for this interim analysis
Progression-Free SurvivalAs determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)n = 453n = 228
Number of events (%)330 (73%)177 (78%)
Median, months7.26.5
(95% CI)(6.7, 8.3)(5.6, 7.4)
Hazard ratio (95% CI)0.75 (0.63, 0.91)
p-value0.0024Compared to the allocated α=0.006 (two sided) for the final PFS analysis
Overall Response Rate,Confirmed responsen = 453n = 228
Number of responders (%)207 (46%)74 (32%)
(95% CI)(41, 50)(26, 39)
Complete Response22 (5%)2 (1%)
Partial Response185 (41%)72 (32%)
Duration of Response,n = 207n = 74
Median, months10.87.8
(95% CI)(9.0, 14.4)(6.8, 10.9)
", "
Table 31: Efficacy Results in OAK
Intravenous AtezolizumabDocetaxel
CI = confidence interval; NE = not estimable
Overall Survival in first 850 patients
Number of patientsN = 425N = 425
Deaths (%)271 (64%)298 (70%)
Median, months13.89.6
(95% CI)(11.8, 15.7)(8.6, 11.2)
Hazard ratioStratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI)0.74 (0.63, 0.87)
p-valueBased on the stratified log-rank test0.0004Compared to the pre-specified allocated α of 0.03 for this analysis
Progression-Free Survival
Number of PatientsN = 425N = 425
Events (%)380 (89%)375 (88%)
Progression (%)332 (78%)290 (68%)
Deaths (%)48 (11%)85 (20%)
Median, months2.84.0
(95% CI)(2.6, 3.0)(3.3, 4.2)
Hazard ratio (95% CI)0.95 (0.82, 1.10)
Overall Response RatePer RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of PatientsN = 425N = 425
ORR, n (%)58 (14%)57 (13%)
(95% CI)(11%, 17%)(10%, 17%)
Complete Response6 (1%)1 (0.2%)
Partial Response52 (12%)56 (13%)
Duration of ResponseN = 58N = 57
Median, months16.36.2
(95% CI)(10.0, NE)(4.9, 7.6)
Overall Survival in all 1225 patients
Number of patientsN = 613N = 612
Deaths (%)384 (63%)409 (67%)
Median, months13.39.8
(95% CI)(11.3, 14.9)(8.9, 11.3)
Hazard ratio (95% CI)0.79 (0.69, 0.91)
p-value0.0013Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary
", "
Table 32: Efficacy Results from IMpower133
Intravenous Atezolizumab with Carboplatin and EtoposidePlacebo with Carboplatin and Etoposide
CI = confidence interval
Overall SurvivalN = 201N = 202
Deaths (%)104 (52%)134 (66%)
Median, months12.310.3
(95% CI)(10.8, 15.9)(9.3, 11.3)
Hazard ratioStratified by sex and ECOG performance status (95% CI)0.70 (0.54, 0.91)
p-valueBased on the stratified log-rank test,Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary0.0069
Progression-Free SurvivalAs determined by investigator assessment,per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)N = 201N = 202
Number of events (%)171 (85%)189 (94%)
Median, months5.24.3
(95% CI)(4.4, 5.6)(4.2, 4.5)
Hazard ratio (95% CI)0.77 (0.62, 0.96)
p-value,Compared to the allocated α of 0.05 for this analysis0.0170
Objective Response Rate,,Confirmed responseN = 201N = 202
Number of responders (%)121 (60%)130 (64%)
(95% CI)(53, 67)(57, 71)
Complete Response (%)5 (2%)2 (1%)
Partial Response (%)116 (58%)128 (63%)
Duration of Response,,N = 121N = 130
Median, months4.23.9
(95% CI)(4.1, 4.5)(3.1, 4.2)
", "
Table 33: Efficacy Results from IMforte
Intravenous Atezolizumab with Lurbinectedin N=242Intravenous Atezolizumab N=241
CI=confidence interval
Overall Survival Measured from the time of randomization
Deaths (%)113 (47%)136 (56%)
Median, months13.210.6
(95% CI)(11.9, 16.4)(9.5, 12.2)
Hazard ratioStratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranial irradiation (95% CI)0.73 (0.57, 0.95)
p-valueBased on the stratified log-rank test, Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis.0.0174
Progression-Free Survival , As determined by an IRF, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of events (%)174 (72%)202 (84%)
Median, months5.42.1
(95% CI)(4.2, 5.8)(1.6, 2.7)
Hazard ratio (95% CI)0.54 (0.43, 0.67)
p-value, Compared to the allocated alpha of 0.001 (two- sided) for this final PFS analysis.<0.0001
", "
Table 34: Efficacy Results from IMbrave150
Intravenous Atezolizumab in combination with Bevacizumab (N= 336)Sorafenib (N=165)
+ Denotes a censored value CI = confidence interval; HCC mRECIST = Modified RECIST Assessment for Hepatocellular Carcinoma; NE = not estimable; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors v1.1
Overall Survival
Number of deaths (%)96 (29)65 (39)
Median OS in monthsNE13.2
(95% CI)(NE, NE)(10.4, NE)
Hazard ratioStratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (< 400 vs. ≥ 400 ng/mL) (95% CI)0.58 (0.42, 0.79)
p-valueBased on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method0.0006
Progression-Free SurvivalPer independent radiology review
Number of events (%)197 (59)109 (66)
Median PFS in months (95% CI)6.8 (5.8, 8.3)4.3 (4.0, 5.6)
Hazard ratio (95% CI)0.59 (0.47, 0.76)
p-value< 0.0001
Overall Response Rate,Confirmed responses (ORR), RECIST 1.1
Number of responders (%)93 (28)19 (12)
(95% CI)(23, 33)(7,17)
p-valueBased on two-sided Cochran-Mantel-Haesnszel test< 0.0001
Complete responses, n (%)22 (7)0
Partial responses, n (%)71 (21)19 (12)
Duration of Response, (DOR) RECIST 1.1
(n=93)(n=19)
Median DOR in monthsNE6.3
(95% CI)(NE, NE)(4.7, NE)
Range (months)(1.3+, 13.4+)(1.4+, 9.1+)
Overall Response Rate, (ORR), HCC mRECIST
Number of responders (%)112 (33)21 (13)
(95% CI)(28, 39)(8, 19)
p-value< 0.0001
Complete responses, n (%)37 (11)3 (1.8)
Partial responses, n (%)75 (22)18 (11)
Duration of Response, (DOR) HCC mRECIST
(n=112)(n=21)
Median DOR in monthsNE6.3
(95% CI)(NE, NE)(4.9, NE)
Range (months)(1.3+, 13.4+)(1.4+, 9.1+)
", "
Table 35: Efficacy Results from IMspire150
Intravenous Atezolizumab + Cobimetinib + Vemurafenib N = 256Placebo + Cobimetinib + Vemurafenib N = 258
Progression-Free SurvivalAs determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI = confidence interval
Number of events (%)148 (58)179 (69)
Median, months15.110.6
(95% CI)(11.4, 18.4)(9.3, 12.7)
Hazard ratioStratified by baseline LDH (95% CI)0.78 (0.63, 0.97)
p-valueBased on the stratified log-rank test0.0249
Overall Response Rate,Confirmed responses
Number of responders (%)170 (66)168 (65)
(95% CI)(60, 72)(59, 71)
Complete responses, n (%)41 (16)46 (18)
Partial response, n (%)129 (50)122 (47)
Duration of Response,n = 170n = 168
Median, months20.412.5
(95% CI)(15.1, NE)(10.7, 16.6)
", "
Table 36: Efficacy Results from Study ML39345
EndpointAll Patients (N=49)
CI: confidence interval; N: number of patients; +: Censored
Overall Response Rate (95% CI)95% CI based on Clopper-Pearson exact method.24% (13, 39)
Complete responses, n0
Partial responses, n (%)12 (24)
Duration of Response
Median, monthNE
(95% CI)(17.0, NE)
Range1+, 41+
Durability of response
≥ 6 months, n (%)8 (67%)
≥ 12 months, n (%)5 (42%)
", "
Table 37: Efficacy Results from IMvigor011
Intravenous Atezolizumab N=167Placebo N=83
CI=confidence interval; NE=not estimable
Investigator-assessed DFS
Number of events (%)112 (67%)66 (80%)
MedianBased on Kaplan-Meier estimates, months9.94.8
(95% CI)(7.2, 12.7)(4.1, 8.3)
Hazard ratioBased on stratified Cox proportional hazards model,Stratified by programmed death-ligand 1 (PD-L1) status, nodal status, tumor stage after cystectomy (95% CI)0.64 (0.47, 0.87)
p-value,Based on stratified log-rank test0.0047
Overall survival
Number of deaths (%)60 (36%) 36 (43%)
Median, months32.821.1
(95% CI)(27.7, NE)(14.7, NE)
Hazard ratio, (95% CI)0.59 (0.39, 0.90)
p-value,0.0131
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING TECENTRIQ HYBREZA (atezolizumab and hyaluronidase-tqjs) injection for subcutaneous use is a sterile, preservative-free, clear to slightly opalescent, and colorless to slightly yellow solution. It is supplied in a carton containing: 1,875 mg and 30,000 units/15 mL (125 mg and 2,000 units/mL) in a single-dose vial (NDC 50242-933-01). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake." ], "storage_and_handling": [ "Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ HYBREZA, including: Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1) ] . Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Warnings and Precautions (5.1) ] . Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1) ] . Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.1) ] . Nephritis: Advise patients to contact their healthcare provider immediately for pelvic pain, frequent urination, or unusual swelling [see Warnings and Precautions (5.1) ] . Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for generalized rash, skin eruption, or painful skin and mucous membrane lesions [see Warnings and Precautions (5.1) ] . Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of other potential immune-mediated adverse reactions [see Warnings and Precautions (5.1) ]. Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs and symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1) ]. Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2) ] . Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT [see Warnings and Precautions (5.3) ] . Embryo-Fetal Toxicity Advise females of reproductive potential that TECENTRIQ HYBREZA can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1 , 8.3) ] . Advise females of reproductive potential to use effective contraception during treatment and for 5 months after the last dose of TECENTRIQ HYBREZA [see Use in Specific Populations (8.3) ] . Lactation Advise female patients not to breastfeed while taking TECENTRIQ HYBREZA and for 5 months after the last dose [see Use in Specific Populations (8.2) ] ." ], "spl_unclassified_section": [ "TECENTRIQ HYBREZA ® (atezolizumab and hyaluronidase-tqjs) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 TECENTRIQ HYBREZA is a registered trademark of Genentech, Inc. ©2026 Genentech, Inc." ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2026 MEDICATION GUIDE TECENTRIQ HYBREZA ® (te-SEN-trik hye-BREEZE-uh) (atezolizumab and hyaluronidase-tqjs) injection, for subcutaneous use What is the most important information I should know about TECENTRIQ HYBREZA? TECENTRIQ HYBREZA is a medicine that may treat certain cancers by working with your immune system. TECENTRIQ HYBREZA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including: Lung problems. cough shortness of breath chest pain Intestinal problems. diarrhea (loose stools) or more frequent bowel movements than usual stools that are black, tarry, sticky, or have blood or mucus severe stomach-area (abdomen) pain or tenderness Liver problems. yellowing of your skin or the whites of your eyes severe nausea or vomiting pain on the right side of your stomach area (abdomen) dark urine (tea colored) bleeding or bruising more easily than normal Hormone gland problems. headaches that will not go away or unusual headaches eye sensitivity to light eye problems rapid heartbeat increased sweating extreme tiredness weight gain or weight loss feeling more hungry or thirsty than usual urinating more often than usual hair loss feeling cold constipation your voice gets deeper dizziness or fainting changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness Kidney problems. decrease in your amount of urine blood in your urine swelling of your ankles loss of appetite Skin problems. rash itching skin blistering or peeling painful sores or ulcers in your mouth or your nose, throat, or genital area fever or flu-like symptoms swollen lymph nodes Problems can also happen in other organs. These are not all of the signs and symptoms of immune system problems that can happen with TECENTRIQ HYBREZA. Call or see your healthcare provider right away for any new or worsening signs or symptoms, including: chest pain, irregular heartbeat, shortness of breath, swelling of ankles confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight persistent or severe muscle pain or weakness, muscle cramps low red blood cells, bruising Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include: chills or shaking itching or rash flushing shortness of breath or wheezing dizziness feeling like passing out fever back or neck pain Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you depending on the type of organ or tissue transplant that you have had. Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TECENTRIQ HYBREZA. Your healthcare provider will monitor you for these complications. Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with TECENTRIQ HYBREZA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TECENTRIQ HYBREZA if you have severe side effects. What is TECENTRIQ HYBREZA? TECENTRIQ HYBREZA is a prescription medicine used to treat: adults with a type of lung cancer called non-small cell lung cancer (NSCLC). TECENTRIQ HYBREZA may be used alone as a treatment for your lung cancer: to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have stage 2 to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and your cancer tests positive for \"PD-L1.\" TECENTRIQ HYBREZA may be used alone as your first treatment when your lung cancer: has spread or grown, and your cancer tests positive for \"high PD-L1,\" and your tumor does not have an abnormal \"EGFR\" or \"ALK\" gene. TECENTRIQ HYBREZA may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer: has spread or grown, and is a type called \"non-squamous NSCLC,\" and your tumor does not have an abnormal \"EGFR\" or \"ALK\" gene. TECENTRIQ HYBREZA may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer: has spread or grown, and is a type called \"non-squamous NSCLC,\" and your tumor does not have an abnormal \"EGFR\" or \"ALK\" gene. TECENTRIQ HYBREZA may also be used alone when your lung cancer: has spread or grown, and you have tried chemotherapy that contains platinum, and it did not work or is no longer working. if your tumor has an abnormal \"EGFR\" or \"ALK\" gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working. adults with a type of lung cancer called extensive-stage small cell lung cancer (SCLC), which is SCLC that has spread and grown. TECENTRIQ HYBREZA may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment. TECENTRIQ HYBREZA may be used with the medicine lurbinectedin as maintenance treatment when your lung cancer: has not progressed after first treatment with TECENTRIQ HYBREZA or intravenous atezolizumab and the chemotherapy medicines carboplatin and etoposide. adults with a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ HYBREZA may be used with the medicine bevacizumab when your liver cancer: has spread or cannot be removed by surgery, and you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer. adults with a type of skin cancer called melanoma. TECENTRIQ HYBREZA may be used with the medicines cobimetinib and vemurafenib when your melanoma: has spread to other parts of the body or cannot be removed by surgery, and has a certain type of abnormal \"BRAF\" gene. Your healthcare provider will perform a test to make sure this TECENTRIQ HYBREZA combination is right for you. adults and children (12 years of age and older and who weigh 88 pounds (40 kg) or more), with a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ HYBREZA may be used alone when your sarcoma has spread to other parts of the body or cannot be removed by surgery. adults with a type of bladder cancer called muscle invasive bladder cancer (MIBC) that has spread into the muscle layer of the bladder but not to other parts of the body. TECENTRIQ HYBREZA may be used alone as a treatment for your bladder cancer: to help prevent your bladder cancer from coming back after your bladder has been removed by surgery, and small pieces of DNA from the tumor (called circulating tumor DNA [ctDNA]) were found in your blood, showing that cancer cells remain in the body (molecular residual disease). Your healthcare provider will perform a test to make sure that TECENTRIQ HYBREZA is right for you. It is not known if TECENTRIQ HYBREZA is safe and effective when used in children: younger than 12 years of age for the treatment of ASPS. for the treatment of NSCLC, SCLC, HCC, melanoma, or MIBC. Who should not receive TECENTRIQ HYBREZA? Do not receive TECENTRIQ HYBREZA if you are allergic to hyaluronidase or any of the ingredients in TECENTRIQ HYBREZA. See the end of this Medication Guide for a complete list of ingredients in TECENTRIQ HYBREZA. Before receiving TECENTRIQ HYBREZA, tell your healthcare provider about all of your medical conditions, including if you: have immune system problems such as Crohn's disease, ulcerative colitis, or lupus have received an organ or tissue transplant, including corneal transplant have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) have received radiation treatment to your chest area have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. TECENTRIQ HYBREZA can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ HYBREZA. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ HYBREZA. You should use an effective method of birth control during your treatment and for 5 months after the last dose of TECENTRIQ HYBREZA. are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ HYBREZA passes into your breast milk. Do not breastfeed during treatment and for 5 months after the last dose of TECENTRIQ HYBREZA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive TECENTRIQ HYBREZA? Your healthcare provider will give you TECENTRIQ HYBREZA as an injection under the skin in the thigh over about 7 minutes. TECENTRIQ HYBREZA is given every 3 weeks. Your healthcare provider will decide how many treatments you need. Your healthcare provider will test your blood to check you for certain side effects. For treatment of a type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. What are the possible side effects of TECENTRIQ HYBREZA? TECENTRIQ HYBREZA can cause serious side effects, including: See \" What is the most important information I should know about TECENTRIQ HYBREZA? \" The most common side effects of TECENTRIQ HYBREZA when used alone in NSCLC include: feeling tired or weak muscle or bone pain cough shortness of breath decreased appetite The most common side effects observed with intravenous TECENTRIQ, which may be experienced with TECENTRIQ HYBREZA are shown below. The most common side effects of TECENTRIQ when used alone as the first treatment for NSCLC include: feeling tired or weak The most common side effects of TECENTRIQ when used alone in NSCLC that has spread or grown include: feeling tired or weak cough decreased appetite shortness of breath muscle or bone pain The most common side effects of TECENTRIQ when used alone in ASPS include: muscle or bone pain feeling tired rash cough headache nausea high blood pressure vomiting constipation shortness of breath dizziness bleeding diarrhea trouble sleeping stomach-area (abdominal) pain low thyroid hormone levels fever anxiety irregular heartbeat (arrhythmia) decreased appetite The most common side effect of TECENTRIQ when used alone in MIBC is urinary tract infection. The most common side effects of TECENTRIQ when used in NSCLC with bevacizumab, paclitaxel, and carboplatin include: numbness, pain, tingling, or burning in your hands or feet feeling tired or weak hair loss muscle or bone pain nausea diarrhea constipation decreased appetite joint pain high blood pressure rash cough The most common side effects of TECENTRIQ when used in non-squamous NSCLC with paclitaxel protein-bound and carboplatin include: feeling tired or weak nausea diarrhea muscle or bone pain constipation numbness, pain, tingling, or burning in your hands or feet hair loss shortness of breath decreased appetite cough vomiting rash The most common side effects of TECENTRIQ when used in SCLC with chemotherapy include: feeling tired or weak nausea hair loss decreased appetite constipation vomiting The most common side effects of TECENTRIQ when used in HCC with bevacizumab include: high blood pressure feeling tired or weak too much protein in the urine The most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include: skin rash joint, muscle or bone pain feeling tired or weak liver injury fever nausea itching swelling of legs or arms mouth swelling (sometimes with sores) low thyroid hormone levels sunburn or sun sensitivity TECENTRIQ HYBREZA may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of TECENTRIQ HYBREZA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of TECENTRIQ HYBREZA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about TECENTRIQ HYBREZA that is written for health professionals. What are the ingredients in TECENTRIQ HYBREZA? Active ingredients: atezolizumab and hyaluronidase-tqjs Inactive ingredients: acetic acid, histidine, methionine, polysorbate 20, sucrose, water for injection. Manufactured by: Genentech, Inc. , A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 USA U.S. License No.: 1048 TECENTRIQ HYBREZA is a registered trademark of Genentech, Inc. For more information, call 1-877-436-3683 or go to www.TECENTRIQHYBREZA.com ." ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 05/2026
MEDICATION GUIDE TECENTRIQ HYBREZA® (te-SEN-trik hye-BREEZE-uh) (atezolizumab and hyaluronidase-tqjs) injection, for subcutaneous use
What is the most important information I should know about TECENTRIQ HYBREZA?
TECENTRIQ HYBREZA is a medicine that may treat certain cancers by working with your immune system. TECENTRIQ HYBREZA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended.
Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:
Lung problems.
coughshortness of breathchest pain
Intestinal problems.diarrhea (loose stools) or more frequent bowel movements than usualstools that are black, tarry, sticky, or have blood or mucussevere stomach-area (abdomen) pain or tenderness
Liver problems.
yellowing of your skin or the whites of your eyessevere nausea or vomitingpain on the right side of your stomach area (abdomen)dark urine (tea colored)bleeding or bruising more easily than normal
Hormone gland problems.
headaches that will not go away or unusual headacheseye sensitivity to lighteye problemsrapid heartbeatincreased sweatingextreme tirednessweight gain or weight lossfeeling more hungry or thirsty than usualurinating more often than usualhair lossfeeling coldconstipationyour voice gets deeperdizziness or faintingchanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems.
decrease in your amount of urineblood in your urineswelling of your anklesloss of appetite
Skin problems.
rashitchingskin blistering or peelingpainful sores or ulcers in your mouth or your nose, throat, or genital areafever or flu-like symptomsswollen lymph nodes
Problems can also happen in other organs. These are not all of the signs and symptoms of immune system problems that can happen with TECENTRIQ HYBREZA. Call or see your healthcare provider right away for any new or worsening signs or symptoms, including:chest pain, irregular heartbeat, shortness of breath, swelling of anklesconfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legsdouble vision, blurry vision, sensitivity to light, eye pain, changes in eyesightpersistent or severe muscle pain or weakness, muscle crampslow red blood cells, bruising
Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:
chills or shakingitching or rashflushingshortness of breath or wheezingdizzinessfeeling like passing outfeverback or neck pain
Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you depending on the type of organ or tissue transplant that you have had. Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TECENTRIQ HYBREZA. Your healthcare provider will monitor you for these complications.
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with TECENTRIQ HYBREZA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TECENTRIQ HYBREZA if you have severe side effects.
What is TECENTRIQ HYBREZA?
TECENTRIQ HYBREZA is a prescription medicine used to treat:adults with a type of lung cancer called non-small cell lung cancer (NSCLC).TECENTRIQ HYBREZA may be used alone as a treatment for your lung cancer:to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, andyou have stage 2 to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), andyour cancer tests positive for "PD-L1."TECENTRIQ HYBREZA may be used alone as your first treatment when your lung cancer:has spread or grown, andyour cancer tests positive for "high PD-L1," andyour tumor does not have an abnormal "EGFR" or "ALK" gene.TECENTRIQ HYBREZA may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, andis a type called "non-squamous NSCLC," andyour tumor does not have an abnormal "EGFR" or "ALK" gene.TECENTRIQ HYBREZA may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:has spread or grown, andis a type called "non-squamous NSCLC," andyour tumor does not have an abnormal "EGFR" or "ALK" gene.TECENTRIQ HYBREZA may also be used alone when your lung cancer:has spread or grown, andyou have tried chemotherapy that contains platinum, and it did not work or is no longer working.if your tumor has an abnormal "EGFR" or "ALK" gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.adults with a type of lung cancer called extensive-stage small cell lung cancer (SCLC), which is SCLC that has spread and grown.TECENTRIQ HYBREZA may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment.TECENTRIQ HYBREZA may be used with the medicine lurbinectedin as maintenance treatment when your lung cancer:has not progressed after first treatment with TECENTRIQ HYBREZA or intravenous atezolizumab and the chemotherapy medicines carboplatin and etoposide.adults with a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ HYBREZA may be used with the medicine bevacizumab when your liver cancer:has spread or cannot be removed by surgery, andyou have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.adults with a type of skin cancer called melanoma. TECENTRIQ HYBREZA may be used with the medicines cobimetinib and vemurafenib when your melanoma:has spread to other parts of the body or cannot be removed by surgery, andhas a certain type of abnormal "BRAF" gene. Your healthcare provider will perform a test to make sure this TECENTRIQ HYBREZA combination is right for you.adults and children (12 years of age and older and who weigh 88 pounds (40 kg) or more), with a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ HYBREZA may be used alone when your sarcoma has spread to other parts of the body or cannot be removed by surgery.adults with a type of bladder cancer called muscle invasive bladder cancer (MIBC) that has spread into the muscle layer of the bladder but not to other parts of the body. TECENTRIQ HYBREZA may be used alone as a treatment for your bladder cancer:to help prevent your bladder cancer from coming back after your bladder has been removed by surgery, andsmall pieces of DNA from the tumor (called circulating tumor DNA [ctDNA]) were found in your blood, showing that cancer cells remain in the body (molecular residual disease). Your healthcare provider will perform a test to make sure that TECENTRIQ HYBREZA is right for you.
It is not known if TECENTRIQ HYBREZA is safe and effective when used in children:younger than 12 years of age for the treatment of ASPS.for the treatment of NSCLC, SCLC, HCC, melanoma, or MIBC.
Who should not receive TECENTRIQ HYBREZA? Do not receive TECENTRIQ HYBREZA if you are allergic to hyaluronidase or any of the ingredients in TECENTRIQ HYBREZA. See the end of this Medication Guide for a complete list of ingredients in TECENTRIQ HYBREZA.
Before receiving TECENTRIQ HYBREZA, tell your healthcare provider about all of your medical conditions, including if you:have immune system problems such as Crohn's disease, ulcerative colitis, or lupushave received an organ or tissue transplant, including corneal transplanthave received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)have received radiation treatment to your chest areahave a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndromeare pregnant or plan to become pregnant. TECENTRIQ HYBREZA can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ HYBREZA. Females who are able to become pregnant:Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ HYBREZA.You should use an effective method of birth control during your treatment and for 5 months after the last dose of TECENTRIQ HYBREZA.are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ HYBREZA passes into your breast milk. Do not breastfeed during treatment and for 5 months after the last dose of TECENTRIQ HYBREZA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive TECENTRIQ HYBREZA?Your healthcare provider will give you TECENTRIQ HYBREZA as an injection under the skin in the thigh over about 7 minutes.TECENTRIQ HYBREZA is given every 3 weeks.Your healthcare provider will decide how many treatments you need.Your healthcare provider will test your blood to check you for certain side effects.For treatment of a type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of TECENTRIQ HYBREZA?
TECENTRIQ HYBREZA can cause serious side effects, including:See "What is the most important information I should know about TECENTRIQ HYBREZA?"
The most common side effects of TECENTRIQ HYBREZA when used alone in NSCLC include:
feeling tired or weakmuscle or bone paincough shortness of breathdecreased appetite
The most common side effects observed with intravenous TECENTRIQ, which may be experienced with TECENTRIQ HYBREZA are shown below. The most common side effects of TECENTRIQ when used alone as the first treatment for NSCLC include:feeling tired or weak
The most common side effects of TECENTRIQ when used alone in NSCLC that has spread or grown include:
feeling tired or weakcoughdecreased appetiteshortness of breathmuscle or bone pain
The most common side effects of TECENTRIQ when used alone in ASPS include:
muscle or bone painfeeling tiredrashcoughheadachenauseahigh blood pressurevomitingconstipationshortness of breathdizzinessbleedingdiarrheatrouble sleepingstomach-area (abdominal) painlow thyroid hormone levelsfeveranxietyirregular heartbeat (arrhythmia)decreased appetite
The most common side effect of TECENTRIQ when used alone in MIBC is urinary tract infection. The most common side effects of TECENTRIQ when used in NSCLC with bevacizumab, paclitaxel, and carboplatin include:
numbness, pain, tingling, or burning in your hands or feetfeeling tired or weakhair lossmuscle or bone painnauseadiarrheaconstipationdecreased appetitejoint painhigh blood pressurerashcough
The most common side effects of TECENTRIQ when used in non-squamous NSCLC with paclitaxel protein-bound and carboplatin include:
feeling tired or weaknauseadiarrheamuscle or bone painconstipationnumbness, pain, tingling, or burning in your hands or feethair lossshortness of breathdecreased appetitecoughvomitingrash
The most common side effects of TECENTRIQ when used in SCLC with chemotherapy include:
feeling tired or weaknauseahair lossdecreased appetiteconstipationvomiting
The most common side effects of TECENTRIQ when used in HCC with bevacizumab include:
high blood pressurefeeling tired or weaktoo much protein in the urine
The most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include:
skin rashjoint, muscle or bone painfeeling tired or weakliver injuryfevernauseaitchingswelling of legs or armsmouth swelling (sometimes with sores)low thyroid hormone levelssunburn or sun sensitivity
TECENTRIQ HYBREZA may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility.
These are not all the possible side effects of TECENTRIQ HYBREZA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of TECENTRIQ HYBREZA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about TECENTRIQ HYBREZA that is written for health professionals.
What are the ingredients in TECENTRIQ HYBREZA?
Active ingredients: atezolizumab and hyaluronidase-tqjs
Inactive ingredients: acetic acid, histidine, methionine, polysorbate 20, sucrose, water for injection. Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 USA U.S. License No.: 1048 TECENTRIQ HYBREZA is a registered trademark of Genentech, Inc. For more information, call 1-877-436-3683 or go to www.TECENTRIQHYBREZA.com.
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